ANTIFUNGAL DRUGS

Prof. Dr. Hanan Hagar MPHL - 232

FUNGAL INFECTIONS
YEAST: Cryptococcus neoformans (Cryptococcosis) Candida albicans (Candidiasis) FILAMENTOUS FUNGI: Tricophyton. Epidermophyton. Aspergillus Microsporum.

DIMORPHIC FUNGI: Histoplasma (Histoplasmosis) Blastomyces (Blastomycosis) Coccidiomyces (Coccidiomycosis) Sporotrichomyces (Sporotrichosis)

ANTIFUNGAL DRUGS
Systemic drugs for systemic infections Amphotericin B Flucytosine Azoles Oral drugs for mucocutaneous infections Griseofulvin Terbinafine

ANTIFUNGAL DRUGS
Topical drugs for mucocutaneous infections Nystatin Topical azoles (miconazole-clotrimazole) Topical allylamines (terbinafine-naftifine)

I. AMPHOTERICIN B
CHEMISTRY:
An amphoteric polyene macrolide antibiotic. Nearly insoluble in water.

PHARMACOKINETICS

Absorption from GIT is poor. 90% is bound to serum protein Most of drug is metabolized slowly in liver. Excretion is slow in urine, takes several days. Plasma half life is 15 days Not dialyzable.

wide distributed in tissues except CNS only 2-3 % of blood level is reached in CSF in meningitis (Intrathecal therapy in fungal meningitis). Drug does cross placenta. Hepatic, renal impairment and dialysis has little effect on drug concentration (No dose adjustment is required).

Pharmaceutical formulations
Conventional formulation Colloidal suspension of amphotericin B + sodium desoxycholate for (I.V. injection). Lipid formulations Liposomal preparations (lipid associated delivery system, I.V.).

Liposomal Amphotericin B
Active drug in lipid delivery vehicles. Lipid vehicles serves as a reservoir reducing binding to human cell membrane. Given I.V. have shorter half life t. larger doses can be used with less toxicity. More expensive

MECHANISM OF ACTION
Selective fungicide acts only against fungal sterol. Binds to ergosterol found in fungal membrane and alter permeability by forming amphotericin B-associated pores leakage of intracellular ions and macromolecules, cell death.

Combination is avid. Amphipathic characteristic. Resistance may occur. Binding to human membrane sterols may occur accounting for drugs toxicity.

Antifungal Activity
Fungicide with the widest spectrum.
Yeast:
Candida albicans Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis

Molds:
Aspergillus fumigatus

Clinical Use
Drug of choice in all life-threatening mycotic infections for serious fungal infection Initial induction regimen replaced later by azole drug. Cancer patients with neutropenia who remain febrile on broad spectrum antibiotics. CNS infections not responding to other drugs Amphotericin B is given by slow I.V. (0.5 1 mg/kg/d to a total dose of 1 2 gm).

Intrathecal therapy for fungal meningitis is poorly tolerated. Mycotic corneal ulcers and keratitis cured by topical drops and subconjunctival injection. Fungal arthritis: intra-articular injection. Candiduria respond to bladder irrigation with no significant systemic toxicity.

Adverse Effects
infusion-related toxicity
Fever, chills, vomiting, muscle spasm, headache, hypotension. Decrease dose or slow the rate. Premedication: antipyretics, antihistaminic, Corticosteroids.

Cumulative toxicity
Renal damage (dose-dependent, reduces renal perfusion, renal tubular injury). Anemia due to reduced erythropoietin. Common practice to administer normal saline infusion with amphotericin B. Abnormal liver function tests.

After Intrathecal therapy: seizures, neurologic damage

II. FLUCYTOSINE (5-FC)

Water soluble pyrimidine analog related to chemotherapeutic agent fluorouracil.

MECHANISM OF ACTION

Drug is taken up by fungal cells via cytosine permease and converted by cytosine deaminase to active metabolite 5-fluorouracil (5-FU) Fluorodeoxyuridine monophosphate (F-dUMP, thymidylate synthase inhibition, DNA synthesis inhibition) Fluorouridine triphosphate (FUTP, substitution for uracil, RNA and protein synthesis inhibition).

Pharmacokinetics of flucytosine

Given orally, well absorbed. Poor protein binding. Wide distribution including CNS Eliminated by glomerular filtration. Half life 3-4 h Removed by hemodialysis. TDM is important in renal insufficiency (50-100 mg/ml).

Spectrum of activity of flucytosine

narrower spectrum of activity than amphotericin B. Restricted to: some Candida species, Cryptococcus neoformans, molds causing Chromoblastomycosis. Not used as single agent. Resistance develops rapidly. Synergism between Fluocytosine and Amphotericin B both in vivo and in vitro. Synergism between fluocytosine and azoles in vitro

Uses of flucytosine
Use is confined to combination therapy Fluocytosine and Amphotericin B for Cryptococcus meningitis Fluocytosine and itraconazole for Chromoblastomycosis

Adverse effects of flucytosine

Toxic effects due to fluorouracil formation (by gut flora). Bone marrow depression, anaemia, leukopenia, thrombocytopenia. Liver enzymes abnormalities. Toxic enterocolitis. Narrow therapeutic window

III. AZOLES Synthetic fungicides

I. IMIDAZOLES: Ketoconazole Miconazole (Topical) Clotrimazole (Topical) II. TRIAZOLES: Itraconazole Fluconazole Voriconazole

Mechanism of Action:
Interferes with cell membrane permeability by decreasing ergosterol synthesis via inhibition of fungal cytochrome P450 (14 -demethylase) required for conversion of lanosterol to ergosterol. Have greater affinity to fungal cytochrome than human.

Mechanism of Action

Mechanism of Action
Imidazoles have lesser degree of specificity than traizoles. Imidazoles have more drug interactions and side effects. Resistance is common.

Spectrum of activity
Broad spectrum of activity: Candida. Cryptococcus neoformans Endemic mycosis (Blastomycosis, histoplasmosis) Dermatophytes. Asperigllus infection (voriconazole & itraconazole)

Adverse effects
Relatively non toxic
Minor GIT upset Liver enzymes abnormalities Drug interactions (varies according to drug)

Ketoconazole
First oral azole. Less selective for fungal P450 than newer drugs. Has greater propensity to inhibit mammalian cytochrome P450 Best absorbed at low gastric pH Useful in treatment of mucocutaneous candidiasis

Adverse effects of ketoconazole

Interferes with biosynthesis of adrenal and gonadal steroid hormones leading to:
Gynaecomastia. Infertility. Menstrual irregularities. Has narrow therapeutic range. Drug interactions

Important Drug Interactions With Ketoconazole:

plasma levels of oral anticoagulants, oral hypoglycemic, phenytoin, cyclosporine. Enhanced arrhythmogenic effect of antihistamine, astimazole and terfenadine. Cimetidine increase gastric pH thereby interfere with absorption of ketoconazole. plasma level. Rifampin increase hepatic metabolism of the azole. plasma level.

Fluconazole
oral, I.V. route. High oral bioavailability Good penetration to CSF. The least microsomal inhibitory effect. Lack of endocrine effect. Renal elimination (dose should be in renal impairment)

Fluconazole
The widest therapeutic window which permits more aggressive dosing. Drug of choice treatment of esophageal & oropharyngeal candidiasis treatment of cryptococcal meningitis in immunodeficient patients. No activity against aspergillus

Itraconazole
Oral-IV Absorption increased by food-low pH Cyclodextran enhance bioavailability Inhibits cyt P450 (lesser than ketoconazole) Drug interactions is less than ketoconazole Reduced bioavailability with rifamycins No effect on mammalian steroids synthesis

Itraconazole
Poor CSF penetration Azole of choice in systemic infections due to dimorphic fungi (histoplasma, blastomyces, sporothrix) Drug of choice in treatment of dermatophytoses active against aspergillus (replaced by voriconazole)

Voriconazole
The newest triazole , Oral- IV Well absorbed, (90% bioavailability) Less protein binding than itraconazole Inhibition of P450 is low The most potent azole Broader spectrum.

Voriconazole
Similar to itraconzole in spectrum Excellent activity against candida, dimorphic fungi and aspergillus infections (the drug of choice for invasive aspergillosis) Rash, elevated hepatic enzymes, visual disturbances

Pharmacologic properties of systemic azole drugs

Uses Absorptio CNS n conc Variable Variable low low t 1/2 hour 710 Elimina Formution lation Hepatic Oral

Ketoconazole Itraconazole

many side effects the drug of choice for dermatophyt oses & dimorphic fungi cryptococcal meningitis candidiasis

2442 Hepatic Oral, IV

Fluconazole

High

Good

2231 Renal

Oral, IV

Voriconazole the drug of choice for invasive aspergillosis

High

low

Hepatic Oral, IV

Echinocandins glucan synthesis inhibitors

The newest class Active against candida and aspergillus but not Cryptococcus neoformans. Caspofungin, micafungin, anidulafungin blocks the synthesis of a major fungal cell wall component, beta (1, 3) glucans leading to disruption of cell wall & cell death used in mucocutaneous candida infections

Mechanism of action
block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase depletion of glucan polymers in the fungal cell weak cell wall unable to withstand osmotic stress cell death

Echinocandins
Minor GIT side effects some drug interactions Caspofungin elevated liver enzymes if combined with with cyclosporine (combination should be avoided) Micafungin cyclosporine, sirolimus, nifedipine Anidulafungin histamine release upon IV infusion

caspofungin Admi nist T1/2 Uses

IV only

micafungin
IV only

anidulafungin
IV only

9-11 h Candida, aspergillus Mucocutaneous candidiasis Invasive aspergillosis Febrile neutropenia

11-15 h Candida, aspergillus Mucocutaneous candidiasis prophylaxis in bone marrow transplants

24-48 h Longest Candida, aspergillus Esophageal & invasive candidiasis

elevated liver enzymes elevated plasma histamine release with cyclosporine levels of cyclosporine, upon IV infusion sirolimus, nifedipine

Oral drugs for mucocutaneous infections

Griseofulvin Terbinafine

I. GRISEOFULVIN
Very insoluble fungistatic drug derived from Penicillium. Orally, Absorption promoted by fatty meal. biliary excretion Oral formulation
MicronizedUltramicrosized

Mechanism of action
Griseofulvin inhibits fungal mitosis by disrupting the mitotic spindle through interaction with polymerized microtubules Only used in systemic treatment of dermatophytosis. It is deposited in newly forming skin where it binds to keratin precursor cells, protecting the skin from new infection.

GRISEOFULVIN
Skin and hair infections (2-6 weeks). Nail infection (longer periods, months) Nausea, diarrhea, headache, skin eruptions and photosensitivity, serum sickness like syndrome, hepatitis. Griseofulvin is microsomal inducer (decrease anticoagulant effect of Warfarin)

II. TERBINAFINE
Synthetic allylamine available in oral formulation- cream. Like griseofulvin, is a keratophilic medication but has fungicidal action.

Mechanism of terbinafine
Acts by interfering with ergosterol biosynthesis like Azole drugs through inhibition of fungal enzyme squalene epoxidase squalene which is toxic to organism. Used in treatment of dermatophytosis especially Onychomycosis (more effective than griseofulvin or itraconazole)

Terbinafine cream is effective for treatment of Tinea cruris and Tinea corporis

Topical antifungal drugs

Topical azoles (clotrimazole, miconazole)
Creams, solution, lotion, vaginal suppositories Oral thrush Vulvovaginal candidiasis Dermatophytic infections (tinea corporis, tinea pedis, tinea cruris). absorption is negligible, rare adverse effects

Topical antifungal drugs

Topical ketoconazole cream, shampoo Treatment of seborrheic dermatitis, pityriasis versicolor

Topical allylamines (terbinafine- naftifine)

Creams, gel Dermatophytic infections (tinea corporis, tinea cruris).

Nystatin
Polyene macrolide antibiotic Too toxic for parenteral administration Creams, ointment, suppositories Not absorbed to a significant degree from skin, mucous membrane, GIT Little toxicity Oral thrush - Vaginal candidiasis