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)