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

topical and i.24 hours) mostly metabolized some is excreted by kidney does not readily pass the bloodbrain barrier .v. (t½ .t..Pharmacokinetics ‡ ‡ ‡ ‡ i.

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 .

chills.hematologic fever. nausea thrombophlebitis hemolytic anemia renal toxicity (severity reduced with sodium loading) hepatic damage hypokalemia .Untoward effects ‡ ‡ ‡ ‡ ‡ ‡ ‡ hypersensitivity-anaphylaxis. headache.

Clinical use of amphotericin ‡Deep-seated fungal infections .

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

H N O N F NH2 Fl c t si .

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 (inhibits thymidylate synthase) RNA 5-FUMP 5-fluorouracil Phosphoribosyl transferase .

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

Pharmacokinetics ‡ Given orally ‡ T ½ ~ 3-6 hours ‡ Penetrates into CNS ‡ Excreted in urine-80% unchanged .

colitis bone marrow suppression thrombocytopenia alopecia decreased liver function . vomiting.Untoward effects ‡ ‡ ‡ ‡ ‡ nausea.

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 Squalene monooxygenase Allylamine drugs Squalene-2.3 oxide Lanosterol 14-E-demethylase Azoles (ergosterol) .

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

Spectrum of imidazoles systemic fungi. dermatophytes fungistatic .

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

abnormal menses ‡ Fluid retention ‡ Hepatitis ‡ Teratogenic ‡ Inhibits drug metabolism ‡ Absorption reduced by H2 antihistamines and omeprazole and antacids .Adverse effects and drug-drug interactions ‡ Nausea. vomiting ‡ Allergic rash ‡ Hormone imbalance.

Triazoles (a type of azole) .

Itraconazole: uses ‡ Histoplasmosis ‡ Sporotrichosis ‡ Aspergillosis ‡ Blastomycosis .

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

similiar to ketoconazole but to lesser degree .Itraconazole: untoward effects ‡ Nausea. vomiting ‡ Liver dysfunction ‡ Hypokalemia ‡ Hypertriglyceridemia ‡ Drug-drug interactions.

headache. rarely liver failure ‡ Least effect of all azoles on liver enzymes ‡ Uses ± cryptococcal meningitis.25 ± 30 hours. rash. N&V.Fluconazole ‡ A triazole ‡ Well absorbed orally. alopecia. coccidioidomycosis . enters CNS ‡ t½ . excreted unchanged ‡ Adverse effects. candidiasis.

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 ‡ Miconazole ‡ Econazole ‡ Oxiconazole ‡ Sertaconazole ‡ Terconazole ‡ Sulconazole ‡ Tioconazole ‡ Butoconazole .

3-epoxidase ‡ Used to treat dermatophyte infections .Allylamines (fungicidal) ‡ Inhibit squalene-2.

3 oxide Lanosterol 14-E-demethylase Azoles (ergosterol) .Acetyl CoA Squalene Squalene monooxygenase Allylamine drugs Squalene-2.

N Terbinafine .

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

Amorolfine. and Butenafine ‡ Other allylamines ‡ For topical use .Naftifine.

. hypokalemia This drug that may be synergistic with amphotericin B and the azoles. It has activity against Candida species and Aspergillus species. 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.Caspofungin ‡ A large cyclic compound ± an echinocandin ‡ Inhibits 1.3-F-D-glucan synthase. histamine release.

Mycafungin Anidulafungin ‡ Echinocandins for candidiasis ‡ Adverse effects are similar to caspofungin .

Griseofulvin (Chemistry) .

fungistatic . ‡ incorporates into keratin and protects newly formed skin.Mechanism of action ‡ binds to microtubules comprising the spindles and inhibits mitosis.

Spectrum ‡ dermatophytes only .

not topically ‡ Microsize and ultramicrosize preparations are used. .Pharmacokinetics ‡ used orally. ‡ 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 .

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

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

Summary of Treatments Pathogen Cryptococcus neoformans Primary Amphotericin B Flucytosine followed by Fluconazole Itraconazole or Amphotericin B Amphotericin B Amphotericin B Itraconazole Secondary Itraconazole or Amphotericin B Histoplasma capsulatum Mucomycosis Sporothrix schenckii Fluconazole Posaconazole SSKI* Updated from Medical Letter. 2005 Saturated solution of potassium iodide .

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