Anti-fungal agents

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 Polyene antibioticsAmphotericin 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 streptomycesnodosus. • 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, Coccidioidesimmitis, Histoplasma, Mucormycosis • It is active against Naegleriafowleriand 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 – amphotericinBcolloidal dispersion • ABLC -- amphotericinBlipid complex

12. ABCD – amphotericinBcolloidal 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 -- amphotericinBlipid complex • ABLC is composed of amphotericin B complexed with dymyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol..

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. Flucytosineis 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 fluorouridinetriphosphate (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 deaminateflucytosine • Well absorbed orally and penetrates into CSF.

19. Anti-fungal agents Flucytosine : Antifungal spectrum Cryptococcus neoformans Candida albicansChromoblastomycosis

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 cutaneouscandidiasisrespond to it Miconazole : effective for tinea, pityriasisVersicolor, candidiasis

35. Anti-fungal agents Griseofulvin : • It is obtained from penicilliumgriseofulvum • It is active againstDermatophytes– 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 -------- 3 weeks Palm and Soles -------- 4 – 6 weeks Finger nails -------- 4 – 6 months Toe nails -------- 8 – 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 squaleneepoxidase – 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 • PityriasisVersicolor • 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. 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)