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FUNGAL INFECTIONS
 Traditionally
have been divided into two
distinct classes: systemic and superficial.
MECHANISM OF ACTION OF
ANTIFUNGALS

Drugs interacting with ergosterol (polyenes)

Drugs inhibiting ergosterol synthesis (azoles,squalene
oxidase inhibitors)

Inhibitors of fungal cell walls (echinocandins)

Inhibitors of fungal mitosis (griseofulvin)

Inhibitors of fungal nucleic acid synthesis (5flucytosine)
DRUGS INTERACTING WITH
ERGOSTEROL
 Polyenes-AmphotericinB,
nystatin
SELECTIVITY
 Selective
 Some
for fungi and not bacteria.
selective toxicity towards fungal
membranes vs mammalian.
RESISTANCE
 Uncommon.
 Probably
content.
results from changes in sterol
INHIBITORS OF ERGOSTEROL
SYNTHESIS
 Azoles
(Demethylase inhibitors)
 Terbinafine
(Squalene oxidase inhibitors)
MECHANISM OF ACTION
 Share
 Either
similar mechanism of action.
fungistatic or fungicidal.
Imidazole
or Triazole
Lanosterol
CH3
Sterol DemethylaseCytochrome P450
dependent enzyme
X
Ergosterol
Mechanism of Action of Imidazoles and Triazoles
AZOLES
 Inhibition
of the demethylase leads to
accumulation of 14--methylsterols.
 Disrupts
the close packing of
phospholipids, impairing the functions of
certain membrane bound enzyme
systems.
AZOLES
 Selective
toxicity towards fungi .
 Imidazoles
(ketoconazole) but not the
triazoles (itraconazole) interact with the
mammalian CYTOCHROME P450
system.
RESISTANCE
 Common
with the newer triazoles.
 The
primary mechanism is accumulation
of mutations in erg11 the gene coding for
the demethylase.
 Cross
resistance to all azoles.
TERBINAFINE (Lamasil)
 Synthetic
allylamine compound that
inhibits ergosterol synthesis.
 Inhibits
squalene epoxidase.
Terbinafine
INHIBITORS OF THE FUNGAL
CELL WALL
CASPOFUNGIN (Candidas)
 Echinocandin
 Blocks
the synthesis of a polysaccharide
component of the cell wall in many fungi
(β-(1,3)-d-glucan).
UDP-glucose
Glucan synthase
Caspofungin
β-1,3 glucan
FUNGAL MITOTIC
INHIBITORS
INHIBITORS OF FUNGAL
NUCLEIC ACID SYNTHESIS
FLUCYTOSINE (Ancobon)
 Flucytosine
is a fluorinated pyrimidine
related to 5-FU.
 Originally
synthesized in 1957 as an
antileukemic agent.
NH2
Flucytosine
N
F
Permease
N
H
O
Fungal Cell
NH2
F
N
O
NH3
5-FU
N
H
5-FdUMP
Cytosine
Deaminase
dUMP
dTMP
MECHANISM OF ACTION
5-FC
5-FU
5-FUTP
RNA
RESISTANCE
 Extensive
if used alone.
POLYENE ANTIFUNGALS
ANTIFUNGAL ACTIVITY
Most species of fungi causing human infections
are susceptible.
 Fungistatic or fungicidal.
 Several different kinds of fungi are sensitive to
amphotericin.

–
–
–
–
pathogenic yeasts
pathogenic yeast-like fungi
dimorphic fungi
molds or filamentous fungi
DRUG FORMULATIONS
 Amphotericin
B deoxycholate (DOC)
administered IV as a colloidal dispersion.
 Lipid
drug formulations for IV infusion
are now available.
DEOXYCHOLATEPHARMACOKINETICS
 Poorly
absorbed from GI tract.
 Prepared
in dextrose, given IV.
 Distributed
to many tissues. It is
sequestered in tissues and slowly
released.
THERAPEUTIC USES
 Systemic
fungal diseases (DOC in the
immunosuppressed).
 Selected
patients with profound
neutropenia and fever unresponsive to
broad-spectrum antibacterial agents.
DRUG INTERACTIONS
 Nephrotoxic
Drugs (e.g. cyclosporine,
aminoglycosides).
 Azole
antifungals.
LIPID FORMULATIONS
 These
preparations differ in the amount
of amphotericin as well as physical form,
serum clearance and acute toxicity.
LIPID FORMULATIONS
 Amphotericin
B lipid complex (ABLC).
 Amphotericin
B colloidal dispersion
(Amphotericin B cholesteryl sulfate
complex, ABCD).
 Liposomal
amphotericin B (Ambisome).
LIPID FORMULATIONS
 Indicated
for systemic infections in
patients unresponsive to the deoxycholate
or who are intolerant of it.
 Less
nephrotoxicity (and less infusion
related events) than the deoxycholate.
 20-50X
as expensive.
5-FC-ANTIFUNGAL ACTIVITY
 Narrow
spectrum of activity (some
Candida species and Cryptococcus
neoformans).
 Most
fungi causing systemic infections
are resistant.
PHARMACOKINETICS
 Rapidly
and well absorbed after oral
administration.
 Widely
distributed throughout the body
including the CNS.
 Mainly
excreted in the urine.
THERAPEUTIC USES
 Usually
used in combination with
Amphotericin B for cryptococcal and
candidal infections.
PRECAUTIONS
 Pregnancy
DRUG INTERACTIONS
 Immunosuppressive
 Nephrotoxic
drugs
drugs
AZOLES

Synthetic compounds.

The imidazoles, miconazole and ketoconazole
were introduced around 1978.

During the 1990s use of ketoconazole
diminished because of the release of the
triazoles-fluconazole and itraconazole (2002voriconazole).
TRIAZOLES
 Enhanced
therapeutic activity and less
toxicity compared to imidazoles.
ANTIFUNGAL ACTIVITY
 Broad
spectrum antifungal agents.
KETOCONAZOLETHERAPEUTIC USES
 Effective
against several systemic fungal
diseases when given orally (several
limitations to its use).
 Dermatophyte
infections.
ITRACONAZOLE (Sporanox)

GI absorption is somewhat erratic and depends
on acidic environment.

Available as capsules and a new oral solution
(about 30% better absorption).

IV preparation now also available.

Metabolized primarily by CYP3A4.
THERAPEUTIC USES
 Serious
fungal diseases in patients
intolerant or refractory to amphotericin .
 Oropharyngeal
and esophogeal
candidiasis.
 Dermatophytoses
and onychomycosis.
DRUG INTERACTIONS
 Many
can occur due to inhibition of CYP
3A4 (e.g. PIs,NNRTIs,anticancer drugs).
FLUCONAZOLE (Diflucan)
 More
favorable pharmacokinetic and
toxicity profiles than itraconazole.
 Relatively
narrow spectrum of activity.
VORICONAZOLE (Vfend)
 Excellent
 Good
oral bioavailability.
activity vs. many fungi
CASPOFUNGINPHARMACOKINETICS
 Given
IV
THERAPEUTIC USES
 Invasive
aspergillosis in patients
resistant to or who can’t tolerate
other antifungals.
 Patients
with oropharyngeal or
esophageal candidiasis.
OCH3
CH3
C
O
O
CH3O
CL
OCH3
GRISEOFULVIN
ANTIFUNGAL ACTIVITY
 Inhibits
the dermatophytes (ringworm
fungi).
 Fungistatic
or fungicidal.
PHARMACOKINETICS
 Variable
oral absorption (Griseofulvin
only works orally).
 Micronized
preparations have the best
absorption.
 Deposited
in keratin precursor cells, new
keratin becomes resistant.
THERAPEUTIC USES
 Treatment
of choice for ringworm
infections (hair, nails, skin, hands etc).
 Length
of therapy depends on location of
the infection.
CONTRAINDICATIONS AND
DRUG INTERACTIONS
 Pregnancy.
 Induces
CYP3A4.
TERBINAFINE
 Used
in the treatment of dermatophyte
infections, especially onychomycosis.
ADVERSE EFFECTS OF THE
ANTIFUNGAL AGENTS
GI UPSET
 Griseofulvin
 Terbinafine
 Flucytosine
 Azoles
NEPHROTOXICITY
Hypomagnesemia
and hypokalemia
AMPHOTERICIN
EFFECTS ON THE BLOOD AND
BONE MARROW
HYPOCHROMIC,NORMOCYTIC ANEMIA
HEMATOLOGIC EFFECTS
 Bone
5-FC
marrow depression is produced by
HEPATOTOXICITY
 Ketoconazole,
 Terbinafine
itraconazole, voriconazole
CNS EFFECTS
 Griseofulvin-headaches,
dizziness
ENDOCRINE EFFECTS
 Imidazoles
but not triazoles produce
impotence, oligospermia etc
INJECTION OR INFUSION
RELATED EFFECTS
 Amphotericin
 Caspofungin
B produces fever and chills
(phlebitis)
THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS
Amphotericin B
Serious systemic fungal diseases
Flucytosine
Crytpcoccosis in AIDS patients,
candidiasis
Itraconazole
Serious systemic fungal diseases
Griseofulvin
Dermatophyte Infections
Terbinafine
Dermatophyte Infections
Caspofungin
Invasive Aspergillosis and
Summary of the Mechanisms and toxicity of the Antifungals
Amphotericin B Bind to ergosterol, Fever and chills,
form pores in
Nephrotoxicity,
fungal membrane Anemia and
Neurotoxicity
Flucytosine
Inhibits fungal
GI, bone marrow
DNA and RNA
depression
synthesis
Imidazoles and Inhibit 14
Ketoconazole-GI,
demethylase (P450 endocrine
Triazoles
enzyme)
Others-GI, liver
Summary of the Mechanisms and Toxicities of the Antifungals
Griseofulvin
Inhibits fungal
mitosis
Terbinafine
Inhibits
GI,
ergosterol
hepatotoxicity
synthesis
Inhibits fungal
Phlebitis
cell wall synthesis
Caspofungin
GI, headache