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Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections are associated with the use of broad spectrum antibiotic,

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Presentation on theme: "Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections are associated with the use of broad spectrum antibiotic,"— Presentation transcript:

1 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.

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


4 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

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

6 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.

7 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.


9 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

10 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.

11 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

12 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.

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

14 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

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

16 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.


18 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.

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

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

21 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 )

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

23 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.


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

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

27 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.

28 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.

29 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.

30 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.

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

32 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

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

34 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

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

36 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

37 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

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

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

40 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


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

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

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

45 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

46 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.

47 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

48 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

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

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

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