antifungal chemotherapy

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INSTITUTE OF HEALTH TECHNOLOGY, DHAKA Department of Laboratory Medicine BSc in Health Technology (Laboratory)- 1 st Year MYCOLOGY Lecture No. 8 (Antifungal Chemotherapy) By Sk. MIZANUR RAHMAN Lecturer, Mycology MS in Biotechnology & Genetic Engineering (UODA) MS in Microbiology (SU)

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Page 1: Antifungal chemotherapy

INSTITUTE OF HEALTH TECHNOLOGY, DHAKADepartment of Laboratory Medicine

BSc in Health Technology (Laboratory)- 1st Year

MYCOLOGY Lecture No. 8 (Antifungal Chemotherapy)

By

Sk. MIZANUR RAHMANLecturer, Mycology

MS in Biotechnology & Genetic Engineering (UODA)MS in Microbiology (SU)

Page 2: Antifungal chemotherapy

Antifungal Chemotherapy

The treatment of disease by the use of chemical substances, especially the treatment of fungal diseases by cytotoxic and other drugs.

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Chemotherapy Types1. Prophylactic – Anti-fungal agents at, or near,

the time of chemotherapy. Posaconazole now approved.2. Empirical – Start therapy when patient at risk,

i.e., fever and/or infiltrate without response to anti-bacterials.

3. Pre-emptive –When there is some additional evidence of fungal infection (serology, isolate, etc.)

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Antifungal agents targeted towards:

Inhibition of fungal cell wall synthesis – caspofungin is a -glucan synthesis inhibitor; several more compounds are under investigation

Inhibition of fungal cell membrane synthesis – ergosterol is the target (cell membranes of fungi and mammals contain different sterols): polyenes, azoles, triazoles, alkylamines

Inhibition of cell division – microtubule effects: griseofulvin; DNA: flucytosine.

Biochemical Targets for Antifungal Chemotherapy

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Antifungal Agents: Families

• Azoles

• Allylamines

• Benzofurans

• Polyenes

• Pyrimidines

• Lipopeptides

Imidazoles Triazoles

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Azole Antifungals for Systemic Infections

• Ketoconazole (Nizoril)• Itraconazole (Sporanox)• Fluconazole (Diflucan)• Voriconazole (Vfend)

Imidazole

Triazoles

“2nd generationtriazole”

Fluconazole Ketoconazole

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The Fungal Cell Wall

mannoproteins

1,6glucans

1,3

chitin

ergosterol

1,3 glucansynthase

Cellmembrane

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

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Antifungal Agents- Sites of action

EchinocandinsInhibit fungal cell wallbiosynthesis

GriseofulvinInhibits mitoticspindle formation

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What are the targets for antifungal therapy?

Cell membraneFungi use principally ergosterol instead of cholesterol

Cell WallUnlike mammalian cells, fungi have a cell wall

DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

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Cell Membrane Active Antifungals

Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical)

• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)

Page 11: Antifungal chemotherapy

Cell Wall Active AntifungalsCell membrane • Polyene antibiotics • Azole antifungals

DNA/RNA synthesis • Pyrimidine analogues - Flucytosine

Cell wall • Echinocandins -Caspofungin acetate (Cancidas)

Page 12: Antifungal chemotherapy

Cell Wall Active Antifungals

Cell membrane • Polyene antibiotics • Azole antifungals

DNA/RNA synthesis • Pyrimidine analogues - Flucytosine

Cell wall • Echinocandins -Caspofungin acetate (Cancidas)

Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001

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Azoles

• Azoles

• Causes Inhibition of C-14 α demethylase, (an enzyme required for the synthesis of ergosterol) by binding to cytochrome P450

Imidazoles Triazoles

Page 17: Antifungal chemotherapy

Allyamines

• Inhibits squalene epoxidase, an enzyme essential for synthesis of ergosterol

• Drug acculmulates in nails, skin and fat

• Very useful for nail infections

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Polyenes

• Amphotericin, nystatin• Antifungal activity by

binding to membrane sterols such as ergosterol and they increase membrane permeability and leads to cell death

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Amphotericin• Numerous forms• Pastilles, Parenteral forms: amphotericin B,

deoxycholate form, colloidal form, Liposomal form• Toxicity: Dose dependent reduction in GFR, by direct

vasoconstritive effect on afferent renal arterioles, destruction of renal tubular cells and basement membrane and loss of functioning units

• Also nausea .vomiting, phlebitis and ACUTE REACTION: fever,chills,tachyapnea

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Pyrimidines• Fluorine analogue of a

normal cell constituent cytosine

• Demination results in 5-fluorouracil, to 5-flurodeoxyuridylic acid monophosphate, a non-competitive inhibitor of thymidylate synthetase

• Used particularly in crytococcal meningitis-74% of serum levels

Page 21: Antifungal chemotherapy

Benzofurans

• Griseofulvin• Inhibits nucleic acid synthesis, macrotubule

formation and chitin formation• Active against ringworm, not candidia or tinea

versicolor

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Lipopeptides

• Echinocandins, derivatives of pneumocandin BO

• Inhibition of ß 1 ,3 glucans in the fungal wall• Active candida, aspergillosis and pneumocystis

carinii

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