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Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections to a large extent are iatrogenic in nature. Fungal infections.

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Presentation on theme: "Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections to a large extent are iatrogenic in nature. Fungal infections."— Presentation transcript:

1 Anti-fungal agents Fungal infections to a large extent are iatrogenic in nature. Fungal infections to a large extent are iatrogenic in nature. Fungal infections are associated with the use of broad spectrum antibiotic, indwelling catheters, AIDS. Fungal infections are associated with the use of broad spectrum antibiotic, indwelling catheters, AIDS. Poor penetration of the drug because fungus infects poorly vascularized. 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. Eukaryotic nature of fungus – resembling human cell makes it difficult treat. Fungus cell wall contains ergosterol whereas mammalian cell contains cholesterol. Fungus cell wall contains ergosterol whereas mammalian cell contains cholesterol.

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4 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) Terbinafine

6 Anti-fungal agents Amphotericin B : It is obtained from streptomyces nodosus. It is obtained from streptomyces nodosus. It has double bonds on one side – lipid soluble. It has OH on other - water soluble It has double bonds on one side – lipid soluble. It has OH on other - water soluble They have amino and carboxyl group. 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. It has affinity for ergosterol present in the cell membrane and forms a micropore thus disrupt the membrane function and cell death.

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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 wide range : Aspergillosis, Candida albicans, Cryptococcus neoformans, Coccidioides immitis, Histoplasma, Mucormycosis It is active against Naegleria fowleri and Leishmaniasis It is active against Naegleria fowleri and Leishmaniasis

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

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

12 ABCD – amphotericin B colloidal dispersion is a lipid formulation of amphotericin B. is a lipid formulation of amphotericin B. the major goal of developing ABCD has been to attain a compound with: 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. 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.. ABLC is composed of amphotericin B complexed with dymyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol..

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

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

16 Flucytosine is a fluorinated pyrimidine Flucytosine is taken up by fungal cells via the enzyme cytosine permease. 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. 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.

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

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

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

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

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

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

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

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

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

28 Anti-fungal agents Ketoconazole : adverse effects : Disulfiram like reaction with alcohol. Disulfiram like reaction with alcohol. It inhibits gonadal and steroid synthesis. It inhibits gonadal and steroid synthesis. It inhibits cyto P450 – dangerous interaction with astemizole, terfenadine and cisapride – resulting in ventricular fibrillation. 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. It has good activity against – Cryptococcus, Coccodioides, Candidiasis. Oral absorption is very good – not dependent on gastric acidity Oral absorption is very good – not dependent on gastric acidity Fungicidal concentration in CNS, saliva and nails. Fungicidal concentration in CNS, saliva and nails.

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

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

32 Anti-fungal agents Itraconazole : Broad spectrum than fluconazole – includes Aspergillus, Blastomyces, Histoplamosis, Tinea, Sporotrichosis. Broad spectrum than fluconazole – includes Aspergillus, Blastomyces, Histoplamosis, Tinea, Sporotrichosis. Inhibits cyto P450 like ketoconazole Inhibits cyto P450 like ketoconazole CNS penetration is poor CNS penetration is poor Impotence is common 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 Effective for topical treatment of tinea infections oral, vaginal and cutaneous candidiasis respond to it 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 obtained from penicillium griseofulvum It is active against Dermatophytes – Epidermatophyton, Trichophyton and Microsporum 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. 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 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 Absorption from the GIT is irregular – better with ultramicrofine granules Better absorption with high fat meals Better absorption with high fat meals It is an inducer of liver enzymes It is an inducer of liver enzymes

38 Anti-fungal agents Griseofulvin : It is used only for the Dermatophytes It is used only for the Dermatophytes Body skin weeks Palm and Soles – 6 weeks Finger nails – 6 months Toe nails – 12 months 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 Headache is the common complaint Peripheral neuritis and Leucopenia Peripheral neuritis and Leucopenia Potentiates the intoxicating effects of alcohol. Potentiates the intoxicating effects of alcohol.

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

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

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

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

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

46 Anti-fungal agents Caspofungin : It is the first approved of Echinocandins 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. 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. Specific for aspergillus and Candida. Excreted by urine and feces Excreted by urine and feces Available for intravenous use only. Available for intravenous use only.

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

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

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

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


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