Antifungal Drugs

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Antifungal Drugs
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Antifungal Drugs Outline

• Polyenes (amphotericin B, nystatin)
• Flucytosine
• Azoles (imidazoles and triazoles)
• Allylamines
• Echinocandins
• Griseofulvin
• Other drugs

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PolyenesAmphotericin B (Fungizone) Chemical
properties - amphoteric aqueous insolubility at
neutral pH
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Mechanism of action

• It binds to fungal membrane sterols (ergosterol)
  and alters permeability selectively to K and
  Mg2. Resistance may develop from altered sterols
  or decreased sterols. It is cidal.

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ergosterol
ergosterol with pore
a polyene
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Pharmacokinetics

• i.v., topical and i.t. (t½ - 24 hours)
• mostly metabolized
• some is excreted by kidney
• does not readily pass the blood- brain barrier

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Spectrum

• most systemic fungi

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Preparations

• Dispersed in deoxycholate
• Lipid formulation (Shape of particles) (type of
  lipid formulation)
• AmBisome (Spheres) (Has complex liposomal
  mixture)
• Amphotec (Disks) (Has cholesteryl sulfate)
• Abelcet (Ribbons) (Has 2 phospholipids)

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Affinity for amphotericin B
Ergosterol
Lipid Formulation
Cholesterol
gt
gt
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Untoward effects

• hypersensitivity-anaphylaxis- hematologic
• fever, chills, headache, nausea
• thrombophlebitis
• hemolytic anemia
• renal toxicity (severity reduced with sodium
  loading)
• hepatic damage
• hypokalemia

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Clinical use of amphotericin

• Deep-seated fungal infections

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Nystatin

• similar to amphotericin B
• used topically and for GI use
• used against candida and dermatophytes
  (Epidermophyton, Trichophyton, Microsporum).

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Mechanism of action

• taken up into the fungal cell by means of
  permease
• converted to 5-fluorouracil (5-FU) by cytosine
  deaminase
• 5-FU eventually inhibits thymidylate synthetase
• synthesized to 5-FUTP
• incorporated into RNA.

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permease
5-flucytosine (outside)
5-flucytosine (inside)
Cytosine deaminase
5-fluorouracil
5dUMP (inhibits thymidylate synthase)
Phosphoribosyl transferase
5-FUMP
RNA
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Uses

• systemic fungi, mainly candida, and
  cryptococcus.
• fungistatic.
• used with amphotericin B (cryptococcal
  meningitis) and with itraconazole
  (chromoblastomyosis).

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Pharmacokinetics

• Given orally
• T ½ 3-6 hours
• Penetrates into CNS
• Excreted in urine-80 unchanged

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Untoward effects

• nausea, vomiting, colitis
• bone marrow suppression
• thrombocytopenia
• alopecia
• decreased liver function

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Azoles

• Imidazoles
• Triazoles

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Ketoconazole
Fluconazole
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Chemistry
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Mechanism of Action

• inhibit the synthesis of ergosterol by blocking
  demethylation (14-demethylase) of lanosterol -
  also inhibit cytochrome activity.

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Acetyl CoA
Squalene
Allylamine drugs
Squalene monooxygenase
Squalene-2,3 oxide
Lanosterol
14-a-demethylase
(ergosterol)
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Resistance

• May develop by altered demethylase or
• by enhanced removal from the fungal cell.

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Spectrum of imidazoles

• systemic fungi, dermatophytes - fungistatic

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Ketoconazole

• blastomycosis, coccidioidomycosis, ringworm,
  candidiasis given orally.
• acid environment is needed to dissolve drug,
  does not enter the CNS well.
• metabolized and has a half-life of 3-6 hrs.
  Mostly fecal excretion after metabolism.

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Adverse effects and drug-drug interactions

• Nausea, vomiting
• Allergic rash
• Hormone imbalance,abnormal menses
• Fluid retention
• Hepatitis
• Teratogenic
• Inhibits drug metabolism
• Absorption reduced by H2 antihistamines and
  omeprazole and antacids

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Triazoles (a type of azole)
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Itraconazole uses

• Histoplasmosis
• Sporotrichosis
• Aspergillosis
• Blastomycosis

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Itraconazole

• variable absorption when given orally,
  metabolized (one active metabolite) approx. 30
  hr. half-life.
• fecal and renal excretion after extensive
  metabolism
• hydroxyitraconazole - an active metabolite.

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Itraconazole untoward effects

• Nausea, vomiting
• Liver dysfunction
• Hypokalemia
• Hypertriglyceridemia
• Drug-drug interactions, similiar to ketoconazole
  but to lesser degree

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Fluconazole

• A triazole
• Well absorbed orally, enters CNS
• t½ - 25 30 hours, excreted unchanged
• Adverse effects- headache, NV, rash, alopecia,
  rarely liver failure
• Least effect of all azoles on liver enzymes
• Uses cryptococcal meningitis, candidiasis,
  coccidioidomycosis

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Voriconazole

• Given iv and orally
• Similar to itraconazole in spectrum
• Little interaction at CYP450

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Posaconazole

• For Invasive candidiasis, aspergillosis and
  Zygomycetes infections
• Only orally available
• Inhibits CYP3A4
• Adverse effects include GI effects, dizziness,
  cardiac arrhythmias, abnormal liver function

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Topical Azoles

• Clotrimazole
• Miconazole
• Econazole
• Oxiconazole
• Sertaconazole

• Terconazole
• Sulconazole
• Tioconazole
• Butoconazole

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Allylamines (fungicidal)

• Inhibit squalene-2,3-epoxidase
• Used to treat dermatophyte infections
•  

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Acetyl CoA
Squalene
Allylamine drugs
Squalene monooxygenase
Squalene-2,3 oxide
Lanosterol
14-a-demethylase
(ergosterol)
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Terbinafine

• Inhibits squalene 2, 3- epoxidase. Squalene is
  cidal to sensitive organisms.
• Used orally for dermatophytes
• Metabolized then excreted in urine
• Adverse effects include hepatitis and rashes.
  Both are rare.

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Naftifine, Amorolfine, and Butenafine

• Other allylamines
• For topical use

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Caspofungin

• A large cyclic compound an echinocandin
• Inhibits 1,3-b-D-glucan synthase, which is
  required for glucan polymerization in the wall of
  certain fungi
• Used for aspergillosis and candidiasis
• Used for empiric antifungal therapy
• Adverse effects fever, histamine release,
  hypokalemia

This drug that may be synergistic with
amphotericin B and the azoles. It has activity
against Candida species and Aspergillus species.
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Mycafungin Anidulafungin

• Echinocandins for candidiasis
• Adverse effects are similar to caspofungin

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Griseofulvin (Chemistry)
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Mechanism of action

• binds to microtubules comprising the spindles
  and inhibits mitosis.
• incorporates into keratin and protects newly
  formed skin. fungistatic

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Spectrum

• dermatophytes only

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Pharmacokinetics

• used orally, not topically
• Microsize and ultramicrosize preparations are
  used.
• Metabolized, then renal excretion
• t½ 24 hours
• Several weeks of therapy are needed.

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Untoward effects

• nausea, headache
• hepatoxicity
• renal toxicity
• photosensitivity
• can precipitate acute intermittent porphyria
• possibly teratogenic
• induces metabolism of some other drugs
• hypersensitivity

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Other Drugs

• ciclopirox olamine - may block amino acid
  transport - penetrates well - useful for candida
  and dermatophytes
• haloprogin - useful for dermatophytes and
  candida, may cause burning
• tolnaftate - useful for dermatophytes - inhibits
  synthesis of macromolecules
• undecylenic acid - dermatophytes
• KI - taken orally for cutaneous sporotrichosis -
  may cause a rash and irritation of salivary and
  lacrimal glands

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Summary of Treatments
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Summary of Treatments
Saturated solution of potassium iodide
Updated from Medical Letter, 2005