2. FUNGAL INFECTIONS
Traditionally have been divided into two distinct classes: systemic and superficial.

3. MECHANISM OF ACTION OF ANTIFUNGALS
Drugs interacting with ergosterol (polyenes)
Drugs inhibiting ergosterol synthesis (azoles,squalene oxidase inhibitors)
Inhibitors of fungal cell walls (echinocandins)
Inhibitors of fungal mitosis (griseofulvin)
Inhibitors of fungal nucleic acid synthesis (5- flucytosine)

4. DRUGS INTERACTING WITH ERGOSTEROL
Polyenes-AmphotericinB, nystatin

7. SELECTIVITY Selective for fungi and not bacteria.
Some selective toxicity towards fungal membranes vs mammalian.

8. RESISTANCE
Uncommon.
Probably results from changes in sterol content.

9. INHIBITORS OF ERGOSTEROL SYNTHESIS
Azoles (Demethylase inhibitors)
Terbinafine (Squalene oxidase inhibitors)

11. MECHANISM OF ACTION Share similar mechanism of action.
Either fungistatic or fungicidal.

13. X Lanosterol Ergosterol Sterol Demethylase- Cytochrome P450
Imidazole
or Triazole X
Lanosterol
Sterol Demethylase-
Cytochrome P450
dependent enzyme
CH3
Ergosterol
Mechanism of Action of Imidazoles and Triazoles

14. AZOLES
Inhibition of the demethylase leads to accumulation of 14--methylsterols.
Disrupts the close packing of phospholipids, impairing the functions of certain membrane bound enzyme systems.

15. AZOLES Selective toxicity towards fungi .
Imidazoles (ketoconazole) but not the triazoles (itraconazole) interact with the mammalian CYTOCHROME P450 system.

16. RESISTANCE Common with the newer triazoles.
The primary mechanism is accumulation of mutations in erg11 the gene coding for the demethylase.
Cross resistance to all azoles.

17. TERBINAFINE (Lamasil)
Synthetic allylamine compound that inhibits ergosterol synthesis.
Inhibits squalene epoxidase.

18. Terbinafine

19. INHIBITORS OF THE FUNGAL CELL WALL

20. CASPOFUNGIN (Candidas)
Echinocandin
Blocks the synthesis of a polysaccharide component of the cell wall in many fungi (β-(1,3)-d-glucan).

21. Glucan synthase
UDP-glucose
β-1,3 glucan
Caspofungin

23. FUNGAL MITOTIC INHIBITORS

25. INHIBITORS OF FUNGAL NUCLEIC ACID SYNTHESIS

27. FLUCYTOSINE (Ancobon)
Flucytosine is a fluorinated pyrimidine related to 5-FU.
Originally synthesized in 1957 as an antileukemic agent.

28. 5-FdUMP Flucytosine NH2 F N Permease O N H Fungal Cell NH2 NH3 F N
Deaminase H
dUMP
dTMP

29. MECHANISM OF ACTION
RNA
5-FC
5-FU
5-FUTP

30. RESISTANCE
Extensive if used alone.

31. POLYENE ANTIFUNGALS

32. ANTIFUNGAL ACTIVITY
Most species of fungi causing human infections are susceptible.
Fungistatic or fungicidal.
Several different kinds of fungi are sensitive to amphotericin.
pathogenic yeasts
pathogenic yeast-like fungi
dimorphic fungi
molds or filamentous fungi

33. DRUG FORMULATIONS
Amphotericin B deoxycholate (DOC) administered IV as a colloidal dispersion.
Lipid drug formulations for IV infusion are now available.

34. DEOXYCHOLATE-PHARMACOKINETICS
Poorly absorbed from GI tract.
Prepared in dextrose, given IV.
Distributed to many tissues. It is sequestered in tissues and slowly released.

36. THERAPEUTIC USES
Systemic fungal diseases (DOC in the immunosuppressed).
Selected patients with profound neutropenia and fever unresponsive to broad-spectrum antibacterial agents.

37. DRUG INTERACTIONS
Nephrotoxic Drugs (e.g. cyclosporine, aminoglycosides).
Azole antifungals.

38. LIPID FORMULATIONS
These preparations differ in the amount of amphotericin as well as physical form, serum clearance and acute toxicity.

39. LIPID FORMULATIONS Amphotericin B lipid complex (ABLC).
Amphotericin B colloidal dispersion (Amphotericin B cholesteryl sulfate complex, ABCD).
Liposomal amphotericin B (Ambisome).

40. LIPID FORMULATIONS
Indicated for systemic infections in patients unresponsive to the deoxycholate or who are intolerant of it.
Less nephrotoxicity (and less infusion related events) than the deoxycholate.
20-50X as expensive.

41. Amphotericin Lipid Formulations
Product
Size (mean diameter)
Configuration
AmBisome
45-80 nm
Small spherical unilamellar liposomes
Amphocil (Amp B colloidal dispersion),
ABCD
115 nm, 4 nm thickness
Disc shaped complexes, with Amp B attached.
Colloidal dispersion of a stable complex of amp with cholesteryl sulfate.
Abelcet (Amp B lipid complex),
ABLC m
Ribbons of lipid with Amp B attached.

42. 5-FC-ANTIFUNGAL ACTIVITY
Narrow spectrum of activity (some Candida species and Cryptococcus neoformans).
Most fungi causing systemic infections are resistant.

43. PHARMACOKINETICS Rapidly and well absorbed after oral administration.
Widely distributed throughout the body including the CNS.
Mainly excreted in the urine.
More than 90% excreted in the urine

44. THERAPEUTIC USES
Usually used in combination with Amphotericin B for cryptococcal and candidal infections.
Use as a single agent is usually precluded

46. PRECAUTIONS
Pregnancy

47. DRUG INTERACTIONS
Immunosuppressive drugs
Nephrotoxic drugs

48. AZOLES Synthetic compounds.
The imidazoles, miconazole and ketoconazole were introduced around 1978.
During the 1990s use of ketoconazole diminished because of the release of the triazoles-fluconazole and itraconazole (2002-voriconazole).

50. TRIAZOLES
Enhanced therapeutic activity and less toxicity compared to imidazoles.

51. ANTIFUNGAL ACTIVITY
Broad spectrum antifungal agents.

52. KETOCONAZOLE-THERAPEUTIC USES
Effective against several systemic fungal diseases when given orally (several limitations to its use).
Dermatophyte infections.

53. ITRACONAZOLE (Sporanox)
GI absorption is somewhat erratic and depends on acidic environment.
Available as capsules and a new oral solution (about 30% better absorption).
IV preparation now also available.
Metabolized primarily by CYP3A4.

54. THERAPEUTIC USES
Serious fungal diseases in patients intolerant or refractory to amphotericin .
Oropharyngeal and esophogeal candidiasis.
Dermatophytoses and onychomycosis.

55. DRUG INTERACTIONS
Many can occur due to inhibition of CYP 3A4 (e.g. PIs,NNRTIs,anticancer drugs).

56. FLUCONAZOLE (Diflucan)
More favorable pharmacokinetic and toxicity profiles than itraconazole.
Relatively narrow spectrum of activity.

57. VORICONAZOLE (Vfend) Excellent oral bioavailability.
Good activity vs. many fungi

58. CASPOFUNGIN-PHARMACOKINETICS
Given IV

59. THERAPEUTIC USES
Invasive aspergillosis in patients resistant to or who can’t tolerate other antifungals.
Patients with oropharyngeal or esophageal candidiasis.

60. OCH3 O
CH3 C O O
CH3O
OCH3 CL
GRISEOFULVIN

61. ANTIFUNGAL ACTIVITY Inhibits the dermatophytes (ringworm fungi).
Fungistatic or fungicidal.

62. PHARMACOKINETICS
Variable oral absorption (Griseofulvin only works orally).
Micronized preparations have the best absorption.
Deposited in keratin precursor cells, new keratin becomes resistant.

63. THERAPEUTIC USES
Treatment of choice for ringworm infections (hair, nails, skin, hands etc).
Length of therapy depends on location of the infection.
Only effective orally. Use when topical therapy failed.

65. CONTRAINDICATIONS AND DRUG INTERACTIONS
Pregnancy.
Induces CYP3A4.

66. TERBINAFINE
Used in the treatment of dermatophyte infections, especially onychomycosis.

68. ADVERSE EFFECTS OF THE ANTIFUNGAL AGENTS

69. GI UPSET
Griseofulvin
Terbinafine
Flucytosine
Azoles

70. NEPHROTOXICITY

71. Hypomagnesemia
and hypokalemia
AMPHOTERICIN

72. EFFECTS ON THE BLOOD AND BONE MARROW

73. HYPOCHROMIC,NORMOCYTIC ANEMIA

74. HEMATOLOGIC EFFECTS
Bone marrow depression is produced by 5-FC

75. HEPATOTOXICITY
Ketoconazole, itraconazole, voriconazole
Terbinafine

76. CNS EFFECTS
Griseofulvin-headaches, dizziness

77. ENDOCRINE EFFECTS
Imidazoles but not triazoles produce impotence, oligospermia etc

78. INJECTION OR INFUSION RELATED EFFECTS
Amphotericin B produces fever and chills
Caspofungin (phlebitis)

79. THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS
Amphotericin B
Serious systemic fungal diseases
Flucytosine
Crytpcoccosis in AIDS patients, candidiasis
Itraconazole
Griseofulvin
Dermatophyte Infections
Terbinafine
Caspofungin
Invasive Aspergillosis and candidiasis

80. Summary of the Mechanisms and toxicity of the Antifungals
Amphotericin B
Bind to ergosterol, form pores in fungal membrane
Fever and chills, Nephrotoxicity, Anemia and Neurotoxicity
Flucytosine
Inhibits fungal DNA and RNA synthesis
GI, bone marrow depression
Imidazoles and
Triazoles
Inhibit 14 demethylase (P450 enzyme)
Ketoconazole-GI, endocrine
Others-GI, liver

81. Summary of the Mechanisms and Toxicities of the Antifungals
Griseofulvin
Inhibits fungal mitosis
GI, headache
Terbinafine
Inhibits ergosterol synthesis
GI, hepatotoxicity
Caspofungin
Inhibits fungal cell wall synthesis
Phlebitis