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ANTI-FUNGAL DRUGS
AGENTSA.Subcutaneous and Systemic Anti-fungalAgents
 –
Amphotericin B
 –
Caspofungin
 –
Flucytosine
 –
Imidazoles: Ketoconazole,Itraconazole, Fluconazole,Miconazole, Voriconazole
 –
Nystatin
 –
 Terbinafine, AmorolfineB.Topical Anti-fungal Agents
 –
Amphotericin B, Butenafine,Butoconazole, Griseofulvin,Ciclopirox, Clioquinol,Clotrimazole, Econazole, Gentianviolet, Ketoconazole, Miconazole,Naftifine, Nystatin, Oxiconazole,Sulconazole, Terbinafine, Terconazole, Tolnaftate
Antifungal Antibiotics
 –
Amphotericin B
 –
Nystatin
 –
Griseofulvin
MECHANISM OF ACTION OF SOME ANTI-FUNGAL DRUGSAMPHOTERICIN B
•
A polyene antibiotic derived fromStreptomyces nodosus.
•
Broad spectrum of activity (C. albicans,H. capsulatum, C. neoformans, C.immitis, aspergillus) both fungistatic andfungicidal activity.
•
MOA:Binds to sterols (ergosterol) in thecell membranes, forming pores orchannels which increase membranepermeability, making the cell moresusceptible to destruction.
•
MOR:Decreased ergosterol content of the fungal membrane.
•
Active in growing and resting cells; nothighly selective and will interfere withmembrane function of mammalian hostcell.Pharmacokinetic profile:
 –
Given by slow IV injection, topical,intrathecal (meningitis) or oral.
 –
Highly CHON-bound; excreted veryslowly through the urine.ADR:Infusion reactions:Fever, shaking chills, hypotension, anorexia,NAV, headache, dyspnea, tachypnea.Others:Renal toxicity (potentiated by sodiumdepletion), electrolyte impairment(hypokalemia, hypomagnesemia,hypocalcemia), normocytic normochromicanemia, impaired hepatic function, localthrombophlebitis; intrathecal
à
neurotoxicity;topical
à
skin rash. Therapeutic Uses:Acute, severe, systemic fungal infections(primary drug – DOC).Local dermatophytic and mucocutaneousinfections (topical).Fungal infections of the GIT (oral).
NYSTATIN
•
Isolated from Streptomyces; firstantimycotic antibiotic.
•
Polyene antibiotic with broad spectrumof activity.
•
MOA:Binds to sterols in fungal cellmembranes, thereby increasingmembrane permeability and making thecell more susceptible to destruction.Pharmacokinetic profile:
 –
Given by oral or topical route.
•
ADR: Local burning and itching (topical).
 
GI upset (NAV, diarrhea), renal toxicity.
•
 Therapeutic Uses: Prevention and topicaltreatment of superficial candidalinfections of the skin and mucousmembranes (gums, GIT, rectum, vagina).
GRISEOFULVIN
•
Fungistatic in activity.
•
MOA: Inhibits fungal cell mitosis by beingaccumulated in the newly-synthesizedkeratin-containing tissue, thus producingmultinucleated defective cells that bindto the microtubules, thereby disruptingmitotic spindle.
•
Pharmacokinetic profile:
 –
Orally administered; t1/2: 24hours.
 –
Distributes to growing nails andskin, binding to keratin andmaking the cells resistant tofungal infection.
 –
Biotransformed in the liver to 6-methyl-griseofulvin; urinary excr.
•
ADR: Headache, lethargy, fatigue,blurred vision,insomnia, GI upset, hepatotoxicity.Drug Interactions:
 –
With anticoagulants
à
reducedeffectiveness of anticoagulantsbecause of enhanced metabolism.
 –
With barbiturates
à
enhancedmetabolism of griseofulvin.
 –
With alcohol
à
tachycardia andflushing; potentiation of intoxicating effects of alcohol.
 –
With oral contraceptives
à
amenorrhea, increasedbreakthrough bleeding. Therapeutic Use:For tinea infections of the skin, hair, nailsincluding athlete’s foot and ringworm causedby Microsporum, Epidermophyton, and Trichophyton (oral).
FLUCYTOSINE
•
Fluorinated pyrimidine derivative forcandidiasis, cryptococcosis, andchromomycosis.
•
Fungistatic, synergistic effect withAmphotericin B.
•
MOA: Converted to 5-FU in sensitivefungi
à
biotransformed to 5-fluoro-deoxyuridylic acid that inhibitsthymidylate synthetase, thus deprivingthe organism of thymidilic acid (essentialDNA component)
à
disrupts DNAsynthesis.
•
MOR:Decreased level of the enzymes inthe conversion of flucytosine to 5-FU.Pharmacokinetic profile:
 –
Administered by oral route; t1/2:3-6 hours. Excretion: Urine.
•
ADR:NAV, diarrhea, rash, anemia,leukopenia, thrombocytopenia;increased liver enzymes, BUN, &creatinine.
SYSTEMIC IMIDAZOLEKetoconazole
•
Broad antifungal activity; fungistaticactivity.
•
MOA:Selectively increases fungal cellmembranepermeability by blocking thedemethylation of lanosterol to ergosterol.(effective only in growing cells)
•
MOR:Mutation in the C14 a-demethylasegene
à
decreased azole binding; fungi’sability to pump the azole out of the cell.
•
Orally given; readily absorbed underacidic pH.
•
ADR:NAV, diarrhea, rash, itching,dizziness,constipation, fever, chills, andheadache; gynecomastia andimpotence; hepatocellular toxicity. Therapeutic Uses:Rx of systemic and vaginal candidiasis,mucocandidiasis, oral thrush, histoplamosis,chromomycosis. coccidioidomycosis,dermatophytosis.
 
Other Azoles
•
Fluconazole
 –
Administered PO or IV.
 –
May produce teratogenic effects.
 –
DOC for Cryptococcusneoformans.
•
Itraconazole
 –
DOC for blastomycosis,aspergillosis, sporotrichosis,histoplasmosis, andparacoccidioidomycosis.
 –
Orally administered.
 –
With teratogenic capability.
•
Voriconazole
 –
Administered orally and effectivefor invasive aspergillosis andserious infections caused byScedosporium apiospermum andfusarium species.
 –
ADR: Transient visual disturbance.
Caspofungin
•
First of the echinocandins class of antifungal drugs.
•
MOA: Interferes with the synthesis of thefungal cell wall by inhibiting thesynthesis of b-D-glucan
à
cell lysis anddeath.
•
ADR: Fever, rash, nausea, phlebitis,flushing.
SYSTEMIC & TOPICAL IMIDAZOLE:Miconazole
•
Administered both parenterally andtopically.
•
 Therapeutic Uses: For Rx of candidal anddermatophytic infections of the skin andfor vaginal candidiasis (topical).For severe systemic fungal infectionsunresponsive or not tolerant to
Amphotericin B (IV)
•
ADR: Local burning, itching, and rash(topical).NAV, anemia, anaphylactoid reactions,CNS toxicity, hyponatremia, phlebitis(IV).
TOPICAL IMIDAZOLEClotrimazole
•
Broad antifungal activity.
•
 Therapeutic Uses: Vulvovaginalcandidiasis (topical) Oropharyngealcandidiasis (topical oral)
•
ADR: Erythema, blistering, edema,pruritus, urticaria. TOPICAL IMIDAZOLESEconazole and Butoconazole
ECONAZOLE
 –
Derivative of miconazole.
 –
Used for the treatment of tinea pedis,tinea cruris, tinea corporis, tineaversicolor, and cutaneous candidiasis.
 –
ADR:Burning, itching, rash.
 –
BUTOCONAZOLE
 –
Azole cream for vaginal use and iseffective against vaginal infectionscaused by Candida albicans andCandida tropicalis.
 –
May cause vulvovaginal burning anditching.
OTHER TOPICAL ANTIMYCOTIC AGENTS
 –
Undecylenic acid, haloprogin.
•
 TERBINAFINE, NAFTIFINE, AMOROLFINE
TERBINAFINE
•
Fungicidal agent that acts by selectivelyinhibiting squalene epoxidase that isinvolved in the synthesis of ergosterolfrom squalene in the fungal cell wall
à
accumulation of squalene
à
toxicity toorganism.
•
Given orally or topically for fungalinfections of the nails.
•
ADR: GI disturbances, rashes, pruritus,headache,dizziness, joint and muscle pains,hepatitis.Related drug:Naftifine 
AMOROLFINE
•
A morpholine derivative that interfereswith fungal sterol synthesis.
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