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

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Presentation on theme: "FUNGAL INFECTIONS  Traditionally have been divided into two distinct classes: systemic and superficial."— Presentation transcript:

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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

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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)

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

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13 Lanosterol Ergosterol Sterol Demethylase- Cytochrome P450 dependent enzyme CH 3 Mechanism of Action of Imidazoles and Triazoles Imidazole or Triazole X

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

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23 FUNGAL MITOTIC INHIBITORS

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25 INHIBITORS OF FUNGAL NUCLEIC ACID SYNTHESIS

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

28 N N O H F NH 2 5-FU 5-FdUMP Permease N N O H NH 2 F dUMPdTMP Flucytosine Fungal Cell Cytosine Deaminase NH 3

29 MECHANISM OF ACTION 5-FU5-FUTP RNA 5-FC

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.

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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 Product Size (mean diameter) Configuration AmBisome 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. Amphotericin Lipid Formulations

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.

44 THERAPEUTIC USES  Usually used in combination with Amphotericin B for cryptococcal and candidal infections.

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46 PRECAUTIONS  Pregnancy

47 DRUG INTERACTIONS  Immunosuppressive drugs  Nephrotoxic drugs

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

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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 GRISEOFULVIN OCH 3 CH 3 O O C O O CH 3 CL

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.

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65 CONTRAINDICATIONS AND DRUG INTERACTIONS  Pregnancy.  Induces CYP3A4.

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

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68 ADVERSE EFFECTS OF THE ANTIFUNGAL AGENTS

69 GI UPSET  Griseofulvin  Terbinafine  Flucytosine  Azoles

70 NEPHROTOXICITY

71 AMPHOTERICIN Hypomagnesemia and hypokalemia

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

80 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 Summary of the Mechanisms and toxicity of the Antifungals

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

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