Transcript Antifungal Agents

Antifungal Agents
Fen-Fei Gao
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.
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Antifungal agents classification:
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Antibiotics: Amphotericin B;
Azole: Ketoconazole;
Allylamine: Terbinafine;
Pyrimidine: Flucytosine.
Antibiotic Antifungal Drugs
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Polyenes: Amphotericin B, Nystatin
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Non-polyenes: Griseofulvin
Amphotericin B
Produced by Streptomyces nodosus.
Amphoteric polyene macrolide.
 Pharmacological Effect: broadspectrum
 Mechanism: binds to ergosterol in
fungi (cholesterol in humans and
bacteria) to form pores
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Pharmacokinetics:
 Poorly absorbed from the gastrointestinal
tract.
 More than 90% bound by serum proteins.
 Metabolized in liver, excreted slowly in the
urine.
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Adverse Effects:
 Infusion-Related Toxicity: fever, chills,
muscle spasms, vomiting, headache,
hypotension.
 Slower Toxicity:
 Renal
toxicity
 K+↓, Mg2+↓
 Anemia: erythropoietin (促红细胞生成素)↓
 Abnormalities of liver function
 Neurologic sequela
 Announcements:
 Administration
in advance of NSAIDs and
Antihistamine drug, Glucocorticoid
 Periodic Monitoring
Liposomal Amphotericin B
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Lipid preparations reduce toxicity
without sacrificing efficacy.
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Lipid formulations distributes mostly
in reticular endothelial tissue (liver,
spleen, lung), but less in kidney.
Nysfungin
Like Amphotericin B and has same
mechanism of action.
 Too toxic for parenteral administration,
and is only used topically (局部).
 Not absorbed from skin, mucous
membranes, or the gastrointestinal
tract, so little significant toxicity.
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Griseofulvin
Derived from a species of penicillium.
 Fungistatic drug (抑菌剂).
 Insoluble.
 Administered in a microcrystalline
form only using in the systemic
treatment of dermatophytosis (脚癣).
 Deposited in newly forming skin where
it binds to keratin (角蛋白), protecting
the skin from new infection.
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Azoles
Synthetic compounds.
 Classification: according to the
number of nitrogen atoms in the fivemembered azole ring
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 Imidazoles: Ketoconazole, Miconazole,
Econazole, Clotrimazole, Bifonazole
 Triazoles: Itraconazole, Fluconazol,
Vorionazole → systemic treatment
Mechanism of Action
Reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450
enzymes.
 Greater affinity for funfal 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.
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Ketoconazole
The first oral azole introduced into
clinical use.
 Less selective for fungal P450
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 Inhibition of human P450 interferes with
biosynthesis of adrenal and gonadal
steroid hormones;
 Alter the metabolism of other drugs.
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Best absorbed at a low gastric pH.
Miconazole, Econazole,
Clotrimazole
Bioavailability is low by taking orally.
 Used topically.
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Bifonazole
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Double inhibition, antifungal action is
more powerful.
Itraconazole
Its absorption is increased by food and
by low gastric pH.
 Treatment of dermatophytoses (皮真菌
病) and onychomycosis (甲真菌病).
 The only agent with significant activity
against aspergillus (曲霉菌) species.
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Fluconazol
Water solubility and good
cerebrospinal fluid penetration.
 The widest therapeutic index (治疗指数)
of the azoles.
 Treatment and secondary prophylaxis
(预防) of cryptococcal meningitis （隐
球菌脑膜炎 ）.
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Vorionazole
Available in an intreavenous and an
oral formulation.
 Metabolism is predominantly hepatic,
but the propensity for inhibition of
mammalian P450 appears to be low.
 Similar to itraconazole in tits spectrum
of action, having good activity against
candida species.
 More effective than itraconazole.
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Acrylamide
Include Naftifine and Terbinafine.
 non-competitive and reversible
inhibitor of Squalene epoxidase.
 Terbinafine is synthetic, oral
formulation.
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 Fungicidal （杀菌剂）
 Treatment of dermatophytoses, especially
onychomycosis, more effective than
griseofulvin or itraconazole.
Pyramine
Flucytosine （5-FC）is 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 aompartments,
including the cerebrospinal fluid.
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Mechanism
 5-FC (taken up by fungal cells via the
enzyme cytosine permease) → 5-FU → FdUMP and FUTP → inhibit DNA and RNA
synthesis, respectively.
Synergy (协同) with amphotericin B.
 Spectrum of action: Cryptococcus
neoformans, some candida species,
and the dematiaceous molds that
cause chromoblastomycosis.
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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)
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 Bone marrow toxicity with anemia,
leukopenia, and thrombocytopenia