Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections are associated with the use of broad spectrum antibiotic, indwelling catheters, AIDS. Poor penetration of the drug because fungus infects poorly vascularized.

Anti-fungal agents Eukaryotic nature of fungus – resembling human cell makes it difficult treat. Fungus cell wall contains ergosterol whereas mammalian cell contains cholesterol.

Drugs for Subcutaneous / Systemic Fungal infections   Drugs for Subcutaneous / Systemic Fungal infections Polyene antibiotics Amphotericin B Echinocandins Caspofungin Pyrimidine antimetabolites Flucytosine Azoles Ketoconazole, Fluconazole, Itraconazole

Drugs for Superficial Fungal infections Systemic drugs Terbinafine Griseofulvin Topical drugs Nystatin Azoles (miconazole, econazole, butaconazole, clotrimazole)

Anti-fungal agents Amphotericin B : It is obtained from streptomyces nodosus. It has double bonds on one side – lipid soluble. It has OH on other - water soluble They have amino and carboxyl group.

Anti-fungal agents Amphotericin B : Mechanism of action : It has affinity for ergosterol present in the cell membrane and forms a micropore thus disrupt the membrane function and cell death.

Anti-fungal agents Amphotericin B : It is active against wide range : Aspergillosis, Candida albicans, Cryptococcus neoformans, Coccidioides immitis, Histoplasma, Mucormycosis It is active against Naegleria fowleri and Leishmaniasis

Anti-fungal agents Amphotericin B : Pharmacokinetics It is not absorbed orally Half life is ~ 15 days Metabolized in liver and excreted in urine and bile Relatively safe in pregnancy.

Anti-fungal agents Amphotericin B : It can be given intravenously and intrathecally New formulations have reduced nephrotoxicity ABCD – amphotericin B colloidal dispersion ABLC -- amphotericin B lipid complex

ABCD – amphotericin B colloidal dispersion is a lipid formulation of amphotericin B. the major goal of developing ABCD has been to attain a compound with: lower toxicity at least similar efficacy compared to the parent compound, amphotericin B deoxycholate. ABCD is composed of amphotericin B complexed with cholesteryl sulfate.

ABLC -- amphotericin B lipid complex ABLC is composed of amphotericin B complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol..

Anti-fungal agents Amphotericin B : Adverse reactions : INFUSION-RELATED TOXICITY Acute reactions (immediate reactions)– related to the infusion of the drug: Fever and chills, muscle spasms, vomiting, headache, and hypotension CUMULATIVE TOXICITY Long term - Nephrotoxicity, anemia, CNS toxicity

Anti-fungal agents Amphotericin is used in : Aspergillosis Coccidioidomycosis Cryptococcosis Candidiasis Histoplasmosis Mucormycosis

Flucytosine is a fluorinated pyrimidine Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

Anti-fungal agents Flucytosine : Fungi static blockade of fungal DNA synthesis Selectivity occurs because mammalian cells do not accumulate and do not deaminate flucytosine Well absorbed orally and penetrates into CSF.

Anti-fungal agents Flucytosine : Antifungal spectrum Cryptococcus neoformans Candida albicans Chromoblastomycosis

Anti-fungal agents Flucytosine : Adverse effects Reversible bone marrow depression ( leukopenia, thrombocytopenia) Liver dysfunction Enterocolitis - rare

Anti-fungal agents Flucytosine : Therapeutic uses Candida infections ( in combination with amphotericin B) Cryptococcal meningitis ( in combination with amphotericin B) Chromoblastomycocis ( in combination with Itraconazole )

Anti-fungal agents Azoles : mainly fungistatic in nature Ketoconazole, Fluconazole, Itraconazole, Voriconazole Clotrimazole, Econazole, Miconazole

Anti-fungal agents Ketoconazole : First orally effective broad spectrum azole anti-fungal agent. Mechanism of action : It inhibits C -14 demethylase thus blocking the demethylation of lanosterol to ergosterol – sterol of fungal membrane.

Anti-fungal agents Ketoconazole : Gastric acidity promotes absorption. Hepatic metabolism is extensive and metabolites are excreted mainly in bile. CNS penetration is poor.

Anti-fungal agents Ketoconazole : Replaced by Itraconazole Anti-fungal spectrum Candidia, Coccidioides, Blastomyces, Histoplasma. Active against dermatophytes also

Anti-fungal agents Ketoconazole : adverse effects : Nausea and vomiting. Hepatitis. Hair loss, gynaecomastia, loss of libido, Oligospermia -- decrease androgen production. Menstrual irregularities in women due to decreased estradiol synthesis.

Anti-fungal agents Ketoconazole : adverse effects : Disulfiram like reaction with alcohol. It inhibits gonadal and steroid synthesis. It inhibits cyto P450 – dangerous interaction with astemizole, terfenadine and cisapride – resulting in ventricular fibrillation.

Anti-fungal agents Fluconazole : Not active against dermatophytes It has good activity against – Cryptococcus, Coccodioides, Candidiasis. Oral absorption is very good – not dependent on gastric acidity Fungicidal concentration in CNS, saliva and nails.

Anti-fungal agents Fluconazole : adverse effects Nausea, skin rash Hepatitis It does not inhibit androgen synthesis Inhibit cyto P 450 metabolizing drugs Not recommended for pregnant women.

Anti-fungal agents Fluconazole : Uses : Candidiasis Disseminated. Cryptococcal meningitis. Coccidioidomycosis.

Anti-fungal agents Itraconazole : Broad spectrum than fluconazole – includes Aspergillus, Blastomyces, Histoplamosis, Tinea, Sporotrichosis. Inhibits cyto P450 like ketoconazole CNS penetration is poor Impotence is common

Anti-fungal agents Voriconazole : Broad spectrum includes aspergillosis. Orally well absorbed Good tissue distribution including – CNS Visual disturbance is the limitation.

Anti-fungal agents Clotrimazole : Effective for topical treatment of tinea infections oral, vaginal and cutaneous candidiasis respond to it Miconazole : effective for tinea, pityriasis Versicolor, candidiasis

Anti-fungal agents Griseofulvin : It is obtained from penicillium griseofulvum It is active against Dermatophytes – Epidermatophyton, Trichophyton and Microsporum

Anti-fungal agents Griseofulvin : Mechanism of action It gets deposited in the keratin forming cells of the skin, hair and nails – especially concentrated and retained in the tinea infected cells – disruption of mitotic spindles - thus interferes with mitosis. Newly formed keratin is not invaded by the fungus

Anti-fungal agents Griseofulvin : Pharmacokinetics : Absorption from the GIT is irregular – better with ultramicrofine granules Better absorption with high fat meals It is an inducer of liver enzymes

Anti-fungal agents Griseofulvin : It is used only for the Dermatophytes Body skin -------- 3 weeks Palm and Soles -------- 4 – 6 weeks Finger nails -------- 4 – 6 months Toe nails -------- 8 – 12 months

Anti-fungal agents Griseofulvin : Headache is the common complaint Peripheral neuritis and Leucopenia Potentiates the intoxicating effects of alcohol.

Anti-fungal agents Terbinafine : Fungicidal Active against dermatophytes and candidiasis Short course of therapy and relapse is poor It acts as a non competitive inhibitor of squalene epoxidase – in the ergosterol synthesis

Anti-fungal agents Terbinafine : Fungicidal Oral absorption – 40 %. It is lipophilic, concentrated in skin and nail.

Anti-fungal agents Terbinafine : adverse effects : Taste and visual disturbances Hepatic dysfunction, hematological disorder No inhibition of cyto P450

Anti-fungal agents Terbinafine : Uses : Topical and Oral Tinea - Onchomycosis - nails Pityriasis Versicolor Candidiasis

Anti-fungal agents NYSTATIN : It is very toxic when given systemically and used only for local anti-fungal effect It is not absorbed orally Used only for oral candidiasis - locally

Anti-fungal agents Caspofungin : It is the first approved of Echinocandins It interferes with the synthesis of fungal cell wall by inhibiting the synthesis of beta ( 1,3 ) D – glucan, leading to cell lysis. Specific for aspergillus and Candida. Excreted by urine and feces Available for intravenous use only.

Anti-fungal agents Other topical anti-fungal agents : Tolnaftate : effective drug for dermatophytes and tinea versicolor Ciclopirox : used for tinea infections, pityriasis versicolor and candidiasis Benzoic acid : anti-fungal agents and anti-bacterial property . Salicylic acid : acts as keratolytic action

Histoplasma capsulatum   Fungi Diseases  Drug(s) of choice Candida species Mucocutaneous thrush Miconazole Nystatin (topical) Fluconazole Deep infection Amphotericin B ± flucytosine Coccidioides immitis Rapid progressing Amphotericin B Meningitis Histoplasma capsulatum Pulmonary Itraconazole

Blastomyces dermatitidis Itraconazole Paracoccidioide brasiliensis Cutaneous and disseminated   Aspergillus fumigatus Invasive Amphotericin B Cryptococcus neoformans Initial Amphotericin B + Flucytosine Maintenance Fluconazole

Terbinafine Griseofulvin   Sporothrix schenckii Cutaneous Itraconazole Extracutaneous Mucormycosis All Amphotericin B Epidermophyton Trichophyton Microsporum Dermatophytoses Terbinafine Griseofulvin Malassezia furfur Tinea versicolor Miconazole (topical)