ANTI-FUNGAL DRUGS

MECHANISMS OF ACTION OF SOME

ANTI-FUNGAL DRUGS

DRUGS/CHEMOTHERAPY

A. Drugs acting on the cell membrane1. Disrupts the integrity of the cell membrane by binding to ergosterol

• Amphotericin B/AMB (fungicidal)- most commonly used

• Nystatin (fungicidal)

DRUGS/CHEMOTHERAPY

2. Interacts with C-14, demethylase to block demethylation of lanosterol to ergosterol

• Imidazole – (Clotrimazole, Ketoconazole, miconazole)

• Triazole (Fluconazole, itraconazole))

DRUGS/CHEMOTHERAPY

B.Nuclear division blocker – Griseofulvin (fungistatic)

C. DNA synthesis blocker – 5 flurocytosine/ 5FC (fungistatic)

SUPERFICIAL MYCOSES: TREATMENT

SUPERFICIAL MYCOSES

TREATMENT

1. Pityriasis Versicolor

2.5% selenium sulfide for 10 min daily for 7 days topical miconazole, itraconazole and ketoconazole

2. Tinea Nigra (Tinea nigra palmaris)

topical keratolytic solutions of sulfur, salicylic acid, or tincture of iodine

3. Black piedra shave or cut the hairs short

4. White piedra shave or cut the hairs short

CUTANEOUS MYCOSES: TREATMENT

body infection – therapy consist of thorough removal of infected and dead epithelial

structures and application of a typical antifungal

chemical (Miconazole, Clotrimazole, Econazole, Ciclopirox) scalp infection – require Griseofulvin nail infection – requires months of griseofulvin treatment and

sometimes surgical removal of the nailFoot Infections

1. Acute phase = soak in potassium permanganate 1: 5,000 until acute inflammation subsides

2. Chronic phase = apply antifungal drug

NYSTATIN Isolated from Streptomyces; first antimycotic antibiotic. Polyene antibiotic with broad spectrum of activity. MOA: Binds to sterols in fungal cell membranes, thereby

increasing membrane permeability and making the cell more susceptible to destruction.

Pharmacokinetic profile: Given by oral or topical route.

ADR: Local burning and itching (topical).GI upset (NAV, diarrhea), renal toxicity (PO).

Therapeutic Uses: Prevention and topical treatment of superficial candidal infections of

the skin and mucous membranes (gums, GIT, rectum, vagina).

MOA OF NYSTATIN

GRISEOFULVIN Fungistatic in activity. MOA: Inhibits fungal cell mitosis by being accumulated in

the newly-synthesized keratin-containing tissue, thus producing multinucleated defective cells that bind to the microtubules, thereby disrupting mitotic spindle.

Pharmacokinetic profile: Orally administered; t1/2: 24 hours. Distributes to growing nails and skin, binding to keratin and

making the cells resistant to fungal infection. Biotransformed in the liver to 6-methyl-griseofulvin; urinary

excr. ADR: Headache, lethargy, fatigue, blurred vision,

insomnia, GI upset, hepatotoxicity.

MOA of Griseolfulvin and the Echinocandins

GRISEOFULVIN

Drug Interactions: With anticoagulants reduced effectiveness of

anticoagulants because of enhanced metabolism. With barbiturates enhanced metabolism of

griseofulvin. With alcohol tachycardia and flushing; potentiation

of intoxicating effects of alcohol. With oral contraceptives amenorrhea, increased

breakthrough bleeding.

Therapeutic Use: For tinea infections of the skin, hair, nails including athlete’s foot and ringworm caused by Microsporum, Epidermophyton, and Trichophyton (oral).

IMIDAZOLES:Ketoconazole

Broad antifungal activity; fungistatic agent. MOA: Selectively increases fungal cell membrane

permeability by blocking the demethylation of lanosterol to ergosterol.

(effective only in growing cells) MOR: Mutation in the C14 -demethylase gene

decreased azole binding; fungi’s ability to pump the azole out of the cell.

Orally given; readily absorbed under acidic pH. ADR: NAV, diarrhea, rash, itching, dizziness,

constipation, fever, chills, and headache; gynecomastia and impotence;

hepatocellular toxicity. Therapeutic Uses: Rx of systemic and vaginal candidiasis,

mucocandidiasis, oral thrush, histoplamosis, chromomycosis, coccidioidomycosis, dermatophytosis.

Azoles FLUCONAZOLE

Administered PO or IV. May produce teratogenic effects. DOC for Cryptococcus neoformans.

ITRACONAZOLE DOC for blastomycosis, aspergillosis, sporotrichosis,

histoplasmosis, and paracoccidioidomycosis. Orally administered. With teratogenic capability.

VORICONAZOLE Administered orally and effective for invasive aspergillosis

and serious infections caused by Scedosporium apiospermum and fusarium species.

ADR: Transient visual disturbance.

Caspofungin First of the echinocandins class of antifungal drugs. MOA: Interferes with the synthesis of the fungal

cell wall by inhibiting the synthesis of -D- glucan cell lysis and death.

ADR: Fever, rash, nausea, phlebitis, flushing.

Others: MicafunginAnidulafungin

For aspergillosis, Pneumocystis carinii infection

SYSTEMIC & TOPICAL IMIDAZOLE: Miconazole Administered both parenterally and topically.

Therapeutic Uses: For Rx of candidal and dermatophytic infections of

the skin and for vaginal candidiasis (topical). For severe systemic fungal infections unresponsive

or not tolerant to Amphotericin B (IV).

ADR: Local burning, itching, and rash (topical).NAV, anemia, anaphylactoid reactions,

CNS toxicity, hyponatremia, phlebitis (IV).

TOPICAL IMIDAZOLE:Clotrimazole

Broad antifungal activity.

Therapeutic Uses: Vulvovaginal candidiasis (topical)Oropharyngeal candidiasis (topical

oral)

ADR: Erythema, blistering, edema, pruritus, urticaria.

TOPICAL IMIDAZOLES:Econazole & Butoconazole

ECONAZOLE Derivative of miconazole. Used for the treatment of tinea pedis, tinea cruris, tinea

corporis, tinea versicolor, and cutaneous candidiasis. ADR: Burning, itching, rash.

BUTOCONAZOLE Azole cream for vaginal use and is effective against vaginal

infections caused by Candida albicans and Candida tropicalis.

May cause vulvovaginal burning and itching.

OTHER TOPICAL ANTIMYCOTIC AGENTS Undecylenic acid, haloprogin.

TERBINAFINE NAFTIFINEAMOROLFINE

TERBINAFINE Fungicidal agent that acts by selectively inhibiting

squalene epoxidase that is involved in the synthesis of ergosterol from squalene in the fungal cell wall accumulation of squalene toxicity to organism.

Given orally or topically for fungal infections of the nails.

ADR: GI disturbances, rashes, pruritus, headache, dizziness, joint and muscle pains,

hepatitis.Related drug: Naftifine

AMOROLFINE A morpholine derivative that interferes with fungal

sterol synthesis. Given orally for fungal infections of the nails.

BUTENAFINE A synthetic benzylamine.

MOA Alters fungal membrane permeability and growth

inhibition. Interferes with sterol biosynthesis by allowing

squalene to accumulate within the cell.

Therapeutic Uses Dermatophytoses, including tinea corporis, tinea

cruris, and tinea pedis (1% cream).

CICLOPIROX

MOA: Intracellular depletion of amino acids and

ions necessary for normal cellular function.

Therapeutic Uses: Tinea pedis, tinea cruris, tinea corporis,

tinea versicolor, cutaneous candidiasis (topical).

CLIOQUINOL, OXICONAZOLE, SULCONAZOLE, TERCONAZOLE

CLIOQUINOL Available in 3% ointment for tinea pedis and cruris. May cause local irritation, rash, and sensitivity reactions.

OXICONAZOLE Available in 1% cream or lotion for tinea cruris, corporis,

mannum, and pedis and tinea versicolor. SULCONAZOLE

Imidazole derivative available in 1% cream or solution and used for tinea corporis, cruris, pedis, versicolor and impetigo.

TERCONAZOLE Imidazole derivative available in vaginal cream and

suppository and used for vulvovaginal candidiasis.

A blissful Christmas and a blessed 2014!