Antifungal Drugs

Antifungal Drugs: Outline

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

Chemical properties - amphoteric

aqueous insolubility at neutral pH
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.
 ergosterol

ergosterol with
pore
+ a polyene
 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
 Spectrum
•most systemic fungi
 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)
 Affinity for amphotericin B

Ergosterol > Lipid Formulation >Cholesterol

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

•Deep-seated fungal
infections
Nystatin
• similar to amphotericin B
• used topically and for GI use
• used against candida and
dermatophytes
(Epidermophyton,
Trichophyton, Microsporum).
 H
N O

N
F

NH2

Flucytosine
 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.
5-flucytosine permease
5-flucytosine
(outside)
(inside)
Cytosine
deaminase

5dUMP 5-fluorouracil
(inhibits
thymidylate
synthase) Phosphoribosyl
transferase
RNA 5-FUMP
 Uses
• systemic fungi, mainly candida, and
cryptococcus.
• fungistatic.
• used with amphotericin B
(cryptococcal meningitis) and with
itraconazole (chromoblastomyosis).
 Pharmacokinetics

• Given orally
• T ½ ~ 3-6 hours
• Penetrates into CNS
• Excreted in urine-80% unchanged
 Untoward effects
• nausea, vomiting, colitis
• bone marrow suppression
• thrombocytopenia
• alopecia
• decreased liver function
 Azoles

• Imidazoles
• Triazoles
Ketoconazole

Fluconazole
Chemistry
Mechanism of Action
inhibit the synthesis of ergosterol by blocking
demethylation (14-demethylase) of lanosterol -
also inhibit cytochrome activity.
 Acetyl CoA

Squalene Allylamine
Squalene
monooxygenase drugs
Squalene-2,3 oxide

Lanosterol
14--demethylase Azoles
(ergosterol)
 Resistance
• May develop by altered
demethylase or
• by enhanced removal from
the fungal cell.
Spectrum of imidazoles
systemic fungi, dermatophytes -
fungistatic
 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.
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
Triazoles (a type of azole)
 Itraconazole: uses
• Histoplasmosis
• Sporotrichosis
• Aspergillosis
• Blastomycosis
 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.
Itraconazole: untoward effects
• Nausea, vomiting
• Liver dysfunction
• Hypokalemia
• Hypertriglyceridemia
• Drug-drug interactions, similiar to
ketoconazole but to lesser degree
 Fluconazole
• A triazole
• Well absorbed orally, enters CNS
• t½ - 25 – 30 hours, excreted unchanged
• Adverse effects- headache, N&V, rash,
alopecia, rarely liver failure
• Least effect of all azoles on liver enzymes
• Uses – cryptococcal meningitis, candidiasis,
coccidioidomycosis
 Voriconazole
• Given iv and orally
• Similar to itraconazole in spectrum
• Little interaction at CYP450
 Posaconazole
• For Invasive candidiasis, aspergillosis and
Zygomycetes infections
• Only orally available
• Inhibits CYP3A4
• Adverse effects include: GI effects,
dizziness, cardiac arrhythmias, abnormal
liver function
 Topical Azoles
• Clotrimazole • Terconazole
• Miconazole • Sulconazole
• Econazole • Tioconazole
• Oxiconazole • Butoconazole
• Sertaconazole
 Allylamines (fungicidal)

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

Squalene Allylamine
Squalene
monooxygenase drugs
Squalene-2,3 oxide

Lanosterol
14--demethylase Azoles
(ergosterol)
N

Terbinafine
 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.
Naftifine, Amorolfine,
and Butenafine
• Other allylamines
• For topical use
 Caspofungin
• A large cyclic compound – an echinocandin
• Inhibits 1,3--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.
 Mycafungin

Anidulafungin
• Echinocandins for candidiasis
• Adverse effects are similar to
caspofungin
Griseofulvin (Chemistry)
Mechanism of action
• binds to microtubules
comprising the spindles and
inhibits mitosis.

• incorporates into keratin and

protects newly formed skin.
fungistatic
 Spectrum

• dermatophytes only
 Pharmacokinetics
• used orally, not topically
• Microsize and ultramicrosize
preparations are used.
• Metabolized, then renal excretion
• t½ ~ 24 hours
• Several weeks of therapy are needed.
 Untoward effects
• nausea, headache
• hepatoxicity
• renal toxicity
• photosensitivity
• can precipitate acute intermittent porphyria
• possibly teratogenic
• induces metabolism of some other drugs
• hypersensitivity
 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
 Summary of Treatments
Pathogen Primary Secondary

Aspergillus Voriconazole Itraconazole,

fumigatus Posaconazole Caspofungin
Amphotericin B
Blastomyces Itraconazole or Fluconazole
dermatidis Amphotericin B
Candida albicans Fluconazole Voriconazole,
Amphotericin B Itraconazole,
Caspofungin Ketoconazole
Posaconazole (topical – many)
Anidulafungin
Coccidioides Itraconazole,
immitis Fluconazole or
Amphotericin B
 Summary of Treatments
Pathogen Primary Secondary

Cryptococcus Amphotericin B ± Itraconazole or

neoformans Flucytosine Amphotericin B
followed by
Fluconazole
Histoplasma Itraconazole or Fluconazole
capsulatum Amphotericin B
Mucomycosis Amphotericin B Posaconazole

Sporothrix Amphotericin B SSKI*

schenckii Itraconazole
Saturated solution of potassium iodide Updated from Medical
Letter, 2005