Antifungal Agents

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Antifungal Agents

• Fen-Fei Gao

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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
• Antibiotics Amphotericin B
• Azole Ketoconazole
• Allylamine Terbinafine
• Pyrimidine Flucytosine.

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Antibiotic Antifungal Drugs

• Polyenes Amphotericin B, Nystatin
• Non-polyenes Griseofulvin

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Amphotericin B

• Produced by Streptomyces nodosus. Amphoteric
  polyene macrolide.
• Pharmacological Effect broad-spectrum
• 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 (???????)?
• Abnormalities of liver function
• Neurologic sequela
• Announcements
• Administration in advance of NSAIDs and
  Antihistamine drug, Glucocorticoid
• Periodic Monitoring

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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.

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Nysfungin

• Like Amphotericin B and has same mechanism of
  action.
• Too toxic for parenteral administration, and is
  only used topically (??).
• 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 (???).
• 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.

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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, Fluconazol, Vorionazole
  ? systemic treatment

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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
• 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.

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Miconazole, Econazole, Clotrimazole

• Bioavailability is low by taking orally.
• Used topically.

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Bifonazole

• Double inhibition, antifungal action is more
  powerful.

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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.

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Fluconazol

• Water solubility and good cerebrospinal fluid
  penetration.
• The widest therapeutic index (????) of the
  azoles.
• Treatment and secondary prophylaxis (??) of
  cryptococcal meningitis (?????? ).

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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.
• Fungicidal (???)
• Treatment of dermatophytoses, especially
  onychomycosis, more effective than griseofulvin
  or itraconazole.

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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 ? F-dUMP and FUTP ?
  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.

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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)
• Bone marrow toxicity with anemia, leukopenia, and
  thrombocytopenia