CHEMOTHERAPEUTICS

Antifungal Drugs
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INTRODUCTION
• Fungi, like mammalian cells but unlike bacteria,
are eukaryotic and possess nuclei,
mitochondria and cell membranes.
• However, their membranes contain distinctive
sterols, ergosterol and lanesterol.
• The very success of antibacterial therapy has
created ecological situations in which
opportunistic fungal infections can flourish.
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• In addition, potent immunosuppressive and
cytotoxic therapies produce patients with seriously
impaired immune defenses, in whom fungi that are
nonpathogenic to healthy individuals become
pathogenic and cause disease.
• Table 45.1 summarizes an approach to antifungal
therapy in immunocompromised patients.
• Sites of action of antifungal drugs are summarized
in Figure 45.1.

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POLYENES
AMPHOTERICIN B
Uses
• Amphotericin is invaluable in treating life-
threatening systemic fungal infections, but
has considerable toxicity.

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• Its spectrum is broad and includes Aspergillus
and Candida species, Blastomyces dermatitidis
(which causes North American blastomycosis),
Histoplasma capsulatum (which causes
histoplasmosis), Cryptococcus neoformans
(which causes cryptococcosis), Coccidioides
immitis (which causes coccidioidomycosis) and
Sporotrichum schenckii (which causes
sporotrichosis).
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• Resistance is seldom acquired.
• Amphotericin is insoluble in water, but can be
complexed to bile salts to give an unstable
colloid which can be administered
intravenously.
• Amphotericin B is normally given as an
intravenous infusion given over four to six
hours.

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• Several liposomal or lipid/colloidal complex
amphotericin preparations have now been formulated,
and are less toxic (particularly less nephrotoxic), but
more expensive than the standard formulation.
• Liposomal amphotericin is reserved for patients who
experience unacceptable adverse effects from regular
amphotericin or in whom nephrotoxicity needs to be
minimized.
• Topical amphotericin lozenges or suspension are used
for oral or pharyngeal candidiasis.

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Mechanism of action
• Amphotericin B binds to ergosterol in the plasma
membranes of sensitive fungal cells.
• There, it forms pores (channels) that require
hydrophobic interactions between the lipophilic
segment of the polyene antifungal and the sterol.
• The pores disrupt membrane function, allowing
electrolytes (particularly potassium) and small
molecules to leak from the cell, resulting in cell
death.
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Pharmacokinetics
• Poor gastro-intestinal absorption necessitates
intravenous administration for systemic infections.
• Amphotericin distributes very unevenly throughout
the body.
• Cerebrospinal fluid (CSF) concentrations are 1/40 of
the plasma concentration, but it is concentrated in the
reticulo-endothelial system.
• The t1/2 is 18–24 hours. Amphotericin elimination is
unaffected by renal dysfunction.
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Adverse effects
• These include:
o fever, chills, headache, nausea, vomiting, and
hypotension during intravenous infusion.
o reversible nephrotoxicity; this is dose dependent
and almost invariable.
o It results from vasoconstriction and tubular
damage leading to acute renal impairment and
sometimes renal tubular acidosis.

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o tubular cationic losses, causing hypokalaemia and
hypomagnesaemia;
o normochromic normocytic anaemia due to
temporary marrow suppression is common.

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NYSTATIN
• Nystatin works in the same way as
amphotericin B, but its greater toxicity
precludes systemic use.
• Its indications are limited to
cutaneous/mucocutaneous and intestinal
infections, especially those caused by Candida
species.

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• Little or no nystatin is absorbed systemically
from the oropharynx or gastrointestinal tract,
and resistance does not develop during therapy.
• Preparations of nystatin include tablets,
pastilles, lozenges or suspension.
• Patients often prefer topical amphotericin B
because nystatin has a bitter taste.
• Cutaneous infections are treated with ointment
and vaginitis is treated by suppositories.
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Adverse effects
• Nystatin can cause nausea and diarrhoea
when large doses are administered orally.

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AZOLES
IMIDAZOLES
• Imidazoles are fungistatic at low concentrations
and fungicidal at higher concentrations.
• They are used topically and are active both
against dermatophytes and yeasts (e.g. Candida).
• Some imidazoles are also used systemically,
although they have limited efficacy and
significant toxicity.
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Mechanism of action of azoles (imidazoles and
triazoles)
• Imidazoles competitively inhibit lanosterol 14-
α-demethylase (a fungal cytochrome-haem
P450 enzyme), which is a major enzyme in the
pathway that synthesizes ergosterol from
squalene.

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• This disrupts the acyl chains of fungal membrane
phospholipids, increasing membrane fluidity and
causing membrane leakage and dysfunction of
membrane-bound enzymes.
• The imidazoles have considerable specificity/affinity
for fungal cytochrome-haem P450 enzymes.
• Azole resistance occurs due to mutations in the gene
encoding for lanosterol 14-α-demethylase (ERG11)
or less commonly due to increased azole efflux by
fungal drug transport proteins.
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• Ketoconazole was the first imidazole to be used
therapeutically but it has been superseded by
newer group members because of its
hepatotoxicity, its incomplete specificity (it inhibits
testosterone and cortisol synthesis) and because it
interacts adversely with many drugs.
• It is still used to treat metastatic prostate cancer
and adrenocortical carcinoma.
• The use and properties of more commonly used
imidazoles are listed in Table 45.2.
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TRIAZOLES
• This group of drugs (e.g. fluconazole,
itraconazole and voriconazole) is derived
from the imidazoles.
• Triazole drugs work by the same mechanism
as imidazoles but have a wider antifungal
spectrum and are more specific for fungal
CYP450.

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FLUCONAZOLE
Uses
• Fluconazole is a potent and broad-spectrum
antifungal agent.
• It is active against many Candida species,
Cryptococcus neoformans and Histoplasma
capsulatum.
• However, Aspergillus species are resistant and
resistant Candida species are problematic in
immunocompromised patients.
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• Fluconazole is used clinically to treat superficial
Candida infections and oesophageal Candida,
for the acute therapy of disseminated Candida,
systemic therapy for blastomycosis and
histoplasmosis, for dermatophytic fungal
infections and, in low doses, for prophylaxis in
neutropenic and immunocompromised patients.
• It is administered orally or intravenously as a
once daily dose.
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Pharmacokinetics
• Fluconazole is well absorbed after oral
administration and is widely distributed
throughout the body.
• CSF concentrations reach 50–80% of those in
the plasma.
• About 80% is excreted by the kidney and dose
reduction is required in renal failure.

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• The fluconazole mean elimination t1/2 is 30
hours in patients with normal renal function.
• Fluconazole is a weaker inhibitor than
ketoconazole of human CYP3A.

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Adverse effects
• Adverse effects include:
o nausea, abdominal distension, diarrhoea and
flatulence;
o rashes, including erythema multiforme;
o hepatitis (rarely, hepatic failure).

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Contraindications
• Fluconazole is contraindicated in pregnancy
because of fetal defects in rodents and
humans.
• Breast milk concentrations are similar to those
in plasma and fluconazole should not be used
by nursing mothers.

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Drug interactions
• Fluconazole reduces the metabolism of several
drugs by inhibiting CYP3A, including
benzodiazepines, calcium channel blockers,
ciclosporin and, importantly, warfarin.
• The plasma concentrations and toxicity of these
drugs will increase during concomitant treatment
with fluconazole.
• Rifampicin enhances the metabolism of
fluconazole.
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ITRACONAZOLE AND VORICONAZOLE
• Itraconazole and voriconazole are available
as oral and parenteral formulations.
• Oral bioavailability is good for both agents, but
intravenous use is indicated for severe fungal
infections.
• The antifungal spectrum is similar to that of
fluconazole and is broad.

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• They are fungicidal at high concentrations.
• Both are metabolized by hepatic CYP450s and
are inhibitors of hepatic CYP450s.
• The mean itraconazole t1/2 is 30–40 hours
and that for voriconazole is six hours.
• For intraconazole, once daily therapy is
adequate though more frequent dosing is
required for voriconazole.

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• Adverse effects include gastro-intestinal
upsets, rashes and hepatitis with rare case of
hepatic failure.
• Voriconazole causes visual disturbances.
• CYP450 (especially CYP3A but CYP2C9 CYP3A
in the case of voriconazole) inhibition related
drug–drug interactions are problematic for
both agents.

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• Drugs which decrease gastric acid (e.g. proton
pump inhibitors) reduce the bioavailability of both
agents and drugs that induce hepatic CYP3A
decrease systemic drug concentrations.
• Neither drug should be used in pregnancy and i.v.
formulations of both should be avoided in patients
with significant renal dysfunction (GFR 30mL/min)
because of accumulation of the drug diluent
(sulphobutylether beta cyclodextrin sodium) which
has nephro- and hepatoxic effects in animals.
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ALLYLAMINES
TERBINAFINE
• Terbinafine is an allylamine and is fungicidal.
• It may be administered orally to treat ringworm
(Tinea pedis, T. cruris or T. corporis) or
dermatophyte infections of the nails.
• It is given once daily for two to six weeks
(longer in infections of the nail bed, as an
alternative to griseofulvin,.
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• It acts by inhibiting the enzyme squalene
epoxidase, which is involved in fungal
ergosterol biosynthesis.

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Pharmacokinetics
• It interferes with human CYP450, but only to a
limited extent (e.g. 10–15% increase in
ciclosporin concentrations).
• It is well absorbed, strongly bound to plasma
proteins and concentrated in the stratum
corneum.
• It is eliminated by hepatic metabolism with a
mean elimination t1/2 of 17 hours.
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• Its major side effects are nausea, abdominal
discomfort, anorexia, diarrhoea and rashes
(including urticaria).
• Dose reduction is needed in hepatic failure or if co-
prescribed with drugs which are potent CYP3A
inhibitors (e.g. HIV protease inhibitors).
• Rifampicin increases terbinafine metabolism,
requiring a dose increase.
• Naftifine, another allylamine, is available for
topical administration.
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ECHINOCANDINS
• Caspofungin and micafungin are novel echinocandins that
are fungicidal to susceptible species.
• Echinocandins are semisynthetic lipopeptides.
Use
• Echinocandins are active against Candida and Aspergillus
species.
• They are used primarily for fungal infections that are
resistant to azoles or where patients are intolerant of
azoles and are administered by intravenous infusion,
usually once daily.
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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.
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Mechanism of action
• Griseofulvin is concentrated in fungi and
binds to tubulin, blocking polymerization of
the microtubule, disrupting the mitotic
spindle.

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Pharmacokinetics
• Griseofulvin is metabolized by the liver to
inactive 6-demethyl griseofulvin, 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.

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Adverse effects
• These include:
o headaches and mental dullness or inattention;
o diarrhoea or nausea;
o rashes and photosensitivity;

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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.

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• 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.

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• 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).

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• It is excreted unchanged by glomerular
filtration (10% of a dose is metabolized).
• The normal t1/2 is six hours and this is
prolonged in renal failure.

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• END

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