DR.

S HANAE GI L L
ANTIFUNGAL AGENTS
OVERVIEW
Fungal infections classification:
Superficial infections: Ringworm (tinea) skin
and mucous membrane. Incidence rate is high.

Systemic infections: Candida albicans
opportunist infections. Fatality rate is high.
Antifungal agents classification:

Polyene: Amphotericin B
Azole: Ketoconazole
Allylamine: Terbinafine
Pyrimidine: Flucytosine
Echinocandins: Capsofungin

ANTIFUNGAL DRUGS

Polyenes: Amphotericin B, Nystatin

Non-polyenes: Griseofulvin
AMPHOTERICIN B
Produced by Streptomyces nodosus. Amphoteric
polyene macrolide.

Pharmacological Effect: broad-spectrum

Mechanism: binds to ergosterol in fungal cell
membrane (cholesterol in humans and bacteria) to
form pores


Pharmacokinetics:

Poorly absorbed from the gastrointestinal tract.
More than 90% bound by serum proteins.
Metabolized in liver, excreted slowly in the urine.
Amphotericin B is very photosensitive and should
be protected from exposure to UV light during
storage and administration.

Adverse Effects:



Infusion-Related Toxicity: fever, chills, muscle spasms,
vomiting, headache, hypotension.


Slower Toxicity:
Renal toxicity
K
+
, Mg
2+

Anemia: erythropoietin
Abnormalities of liver function
Neurologic sequelae
LIPOSOMAL AMPHOTERICIN B
Lipid preparations reduce toxicity without
sacrificing efficacy.

Lipid formulations distributes mostly in reticular
endothelial tissue (liver, spleen, lung), but less in
kidney.
NYSTATIN
Like Amphotericin B and has same mechanism of
action.
Too toxic for parenteral administration, and is only
used topically.
Common (and old) topical agent for candidiasis

Not absorbed from skin, mucous membranes, or the
gastrointestinal tract, so little significant toxicity.

GRISEOFULVIN
Derived from a species of penicillium.

Fungistatic- disrupts microtubule formation and
inhibits mitosis

Insoluble.

Administered in a microcrystalline form only using in
the systemic treatment of dermatophytosis.

Deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection.
AZOLES
Synthetic compounds.

Classification: according to the number of nitrogen
atoms in the five-membered azole ring

Imidazoles: Ketoconazole, Miconazole, Econazole,
Clotrimazole, Bifonazole

Triazoles: Itraconazole, Fluconazole, Vorionazole
systemic treatment
MECHANISM OF ACTION
Reduction of ergosterol synthesis by inhibition of
fungal cytochrome P450 enzymes.

Greater affinity for fungal than for human
cytochrome P450 enzymes.

Imidazoles exhibit a lesser degree of specificity
than the triazoles, accounting for their higher
incidence of drug interactions and side effects.
KETOCONAZOLE
The first oral azole introduced into clinical use.
Less selective for fungal P450

Inhibition of human P450 interferes with biosynthesis of
adrenal and gonadal steroid hormones;

Alter the metabolism of other drugs.

Best absorbed at a low gastric pH.
KETOCONAZOLE SHAMPOO

MICONAZOLE, ECONAZOLE,
CLOTRIMAZOLE
Bioavailability is low by taking orally.
Used topically.
ITRACONAZOLE
Its absorption is increased by food and by low
gastric pH.

Treatment of dermatophytoses and onychomycosis

The only agent with significant activity against
aspergillus species.
FLUCONAZOLE
Water solubility and good cerebrospinal fluid
penetration.

The widest therapeutic index of the azoles.

Treatment and secondary prophylaxis of
cryptococcal meningitis.
ACRYLAMIDE
Include Naftifine and Terbinafine.
non-competitive and reversible inhibitor of
Squalene epoxidase [catalyzes the first oxygenation step
in sterol biosynthesis .]

Terbinafine is synthetic, oral formulation.
Fungicidal

Treatment of dermatophytoses, especially onychomycosis,
more effective than griseofulvin or itraconazole.
TERBINAFINE

PYRAMINE
Flucytosine 5-FCis a water-soluble pyrimidine
analog.

Its spectrum of action is much narrower than that of
amphotericin B.

Poorly protein-bound and penetrates well into all
body fluid compartments, including the
cerebrospinal fluid.
Mechanism

5-FC (taken up by fungal cells via the enzyme cytosine
permease) 5FU 5 fluro UMP inhibit DNA and RNA
synthesis, respectively.

Synergy with amphotericin B.

Spectrum of action: Cryptococcus neoformans,
some candida species, and the dematiaceous
molds that cause chromoblastomycosis.
Not used as a single agent because of its
demonstrated synergy with other agents and to
avoid the development of secondary resistance.

Adverse effects: result from metabolism to
fluorouracil (5-FU)
Bone marrow toxicity with anemia, leukopenia, and
thrombocytopenia
FLUCYTOSINE

ECHINOCANDINS
inhibit the synthesis of glucan in the cell wall, via
noncompetitive inhibition of the enzyme 1,3-
glucan synthase

Glucan- carbohydrate polymers which are cross-
linked with other fungal cell wall components

Used for aspergillosis and Candidiasis

Examples :Capsofungin
ADVERSE EFFECTS

Embryotoxic cannot be used in pregnancy

needs dose adjustment in liver disease

OVERVIEW

OVERVIEW