This document provides an overview of anti-fungal drugs. It begins by classifying antifungals based on their chemical structure, sites of action, and mechanisms of action. The major classes discussed include azoles, polyene macrolides, and other antifungals. Azoles like fluconazole and itraconazole are broad-spectrum and inhibit ergosterol synthesis. Amphotericin B binds to ergosterol and forms pores in fungal membranes. Other antifungals discussed are flucytosine, griseofulvin, and nystatin. The document outlines the mechanisms, therapeutic uses, and adverse effects of the main antifungal drug

1. Anti-Fungal Drugs
Dr. Sameh Ahmad Muhamad abdelghany
Lecturer Of Clinical Pharmacology
Mansura Faculty of medicine

2. Lecture objectives
By the end of this lecture the students should be
able;
 To give major groups and specific examples of
the antifungal drugs.
 To describe the mechanisms of action
antifungal drugs including their
pharmacological effects.
 To outline clinical applications of the drugs in
medicine.
2

3. Lecture outline
3
1
Introduction
2 Classification Of
Antifungals
3
Azoles
4 Polyene Macrolides
antifungals
5 Other antifungal drugs

4. INTRODUCTION

5. Introduction
 Pathogenic fungi of animals and humans are generally
filamentous molds or intracellular yeasts.
 The fungal cell wall contains chitin and polysaccharides
making it rigid, and acts as a barrier to drug penetration.
 The cell membrane contains ergosterol, which influences the
efficacy and the risk of drug resistance.
 Most antifungal agents are fungistatic with infection-
clearance largely dependent on host response.
5

7. FUNGI
Fungi may be classified as
 Yeasts: Blastomyces, candida, histoplasma,
coccidioides,cryptococcus.
 Moulds: Aspergillus spp. , Dermatophytes
Clinically classified as:
 Superficial mycosis
 Deep (systemic) mycosis
7

8. FUNGI
8

9. Fungal Infection in Humans = Mycosis
Major Types of Mycoses
 superficial
 cutaneous
 subcutaneous
 systemic
 opportunistic
Symptoms vary from cosmetic to life threatening
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10. Types of fungal infections
10
I. Mucocutaneous (superficial)
infections:
a. Dermatophytes:
 cause infection of skin, hair, and
nails
 e.g. tinea capitis (scalp), tinea
cruris (groin), tinea pedis (foot),
onychomycosis (nails).

11. Types of fungal infections
11
b. Yeasts:
 cause infections of moist skin and
mucous membranes
 e.g. Candida albicans causing oral,
pharyngeal, vaginal, & bladder
infections

12. Types of fungal infections
12
II. Systemic mycoses:
 are fungal infections affecting
internal organs.
 It occurs in immunocompromized
patients e.g. cryptococcosis, and
aspergillosis (lung).

13. CLASSIFICATION OF
ANTIFUNGALS

14. Classification of antifungal drugs
 Based on chemical structures:
 The classes include Polyene macrolides, Imidazoles,
Fluorinated pyrimidines, Benzo-furans and Iodides
 Based on their sites of action:
 Either systemic or topical antifungal drugs.
 Miscellaneous classifications:
 Organic acids and their salts and other inorganic salts
14

15. Classification of antifungal drugs
15
I. Drugs for mucocutaneous infections:
i. Systemic drugs
 Azoles: Fluconazole, Itraconazole, Voriconazole.
 Griseofulvin
 Terbinafine

16. Classification of antifungal drugs
16
ii. Topical drugs
 Azoles: Ketoconazole, Miconazole, Clotrimazole,
Tioconazole, etc.
 Nystatin
 Terbinafine.
 Other drugs: Tolnaftate, Ciclopirox, Naftifine, Whitfield
ointment, Gentian violet, Castellani paint, Tincture
iodine.

17. Classification of antifungal drugs
17
II. Drugs for Systemic infections: :
 Azoles: Fluconazole, Itraconazole, Voriconazole.
 Amphotericin-B
 Flucytosine
 Caspofungin

18. Classification based on mechanism of
action
18
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin.
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine,
Butenafine.
4. Inhibition of ergosterol synthesis: Azoles
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis:
Griseofulvin.
7. Miscellaneous: Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid,
Topical azoles

20. Classification based on structure
20
 ANTIBIOTICS
 Polyene: Amphotericin, nystatin, hamycin
 Hetrocyclic benzofuran: griseofulvin
 ANTIMETABOLITE : Flucytosine
 AZOLES
 Imidazoles: Ketoconazole, clotrimazole, oxiconazole,miconazole,
 Triazoles: Fluconazole, itraconazole, voriconazole,

21. Classification based on structure
21
 ALLYLAMINES
 Terbinafine, butenafine
 ECHINOCANDINS
 Caspofungin, anidulafungin, micafungin
 OTHER TOPICALAGENTS
 Tolnaftate, Undecyclinic acid, benzoic acid

22. I- Azoles
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 Chemistry
 Ketoconazole, Miconazole, Fluconazole, Itraconazole,
Voriconazole

23. I- Azoles
23
 Synthetic antifungals
 Broad spectrum
 Fungistatic or fungicidal depending on conc of drug
 Most commonly used
 Classified as imidazoles & triazoles

24. I- Azoles
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I. Imidazoles: Two nitrogen in structure
o Topical: econazole, miconazole, clotrimazole
o Systemic : ketoconazole
o Newer : butaconazole, oxiconazole, sulconazole
II. Triazoles : Three nitrogen in structure
o Fluconazole, itraconazole, voriconazole
o Terconazole: Topical for sup

25. Azoles
25
 Pharmacokinetics
 Absorption of azoles from stomach is affected by food
and gastric HCl.
 Fluconazole can reach the CSF with good concentrations.
The other drugs cannot.
 Fluconazole is excreted in the urine mostly unchanged

26. Azoles
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Mechanism of action
 Azoles inhibit fungal cytochrome P450
(14 α demthylase )necessary for ergosterol
synthesis, a major component of fungal cell
membrane. This will alter membrane
permeability and disrupt its function.
 are broad spectrum fungistatic against
many dermatophytes and candida.

27. 27

28. Azoles
28
 Therapeutic uses
I. Superficial fungal infections: [ketoconazole – itraconazole –
miconazole]
1. Dermatophytes infection of the skin (tinea), hair, and nails
(onychomycosis):
 For skin infection: treatment continued for 2-4 weeks.
 For hair infection: treatment continued for 6-8 weeks.
 For nail infection: treatment continued for 3-6 months.
2. Mucocautaneous candidiasis: oropharyngeal, vulvovaginal, etc.

29. Azoles
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II. Systemic fungal infections: [itraconazole – fluconazole –
voriconazole]
 Itraconazole (orally or IV) is the drug of choice for systemic
blastomycosis.
 Fluconazole (orally or IV) is the drug of choice for systemic
candidiasis, and cryptococcal meningitis (because it the only azole
that can cross to CSF with good concentration).
 Voriconazole is the drug of choice for inVasive aspergillosis of the
lung.

30. Azoles
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 Adverse effects
1. Hepatotoxicity and ↑ of serum transaminases.
2. Azoles inhibit hepatic CYP450 enzymes
(fluconazole is the least among them).
3. Ketoconazole causes antianderogenic
effects: gynecomastia and impotence due to
↓ gonadal steroid synthesis.
4. Voriconazole causes transient Visual
disturbances.

31. II- Amphotericin-B
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 Chemistry
 Obtained from Streptomyces Nodosus
 Amphoteric in nature

32. Amphotericin-B
32
 Pharmacokinetics
 is polar compound that cannot be absorbed from the
GIT or cross the CSF.
 Insoluble in water so colloidal suspension prepared
with sodium deoxycholate(1:1 complex)
 90% bound to plasma proteins
 It should be administered IV or intrathecal.
 Half-life is 15 days.
 Dialysis is ineffective in case of toxicity.

33. Amphotericin-B
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 Pharmacokinetics(cont.)
 Because of significant toxicity, amphotericin B is
available in liposomal form in which the drug is enclosed
in lipid microspheres “liposomes”.
 These lipid microspheres bind preferentially to ergosterol
in the fungal cell membrane with lower affinity to
mammalian cell membranes.

34. Amphotericin-B
34
 Mechanism of action
 Amphotericin B is polyene macrolide that binds to
ergosterol of fungal cell membranes and forms “pores”
that alter membrane stability and allow leakage of
cellular contents.

36. Amphotericin-B
36
 Therapeutic uses
 Amphotericin B has the broadest spectrum of activity.
o Treat severe Systemic fungal infections, including
those caused by Candida albicans, Histoplasma
capsulatum, Cryptococcus neoformans, Coccidioides
immitis, Blastomyces dermatitidis and Aspergillus spp.

37. 37
 Adverse effects
I. Acute reaction:
 Chills, fever, headache, pain all over, nausea, vomiting,
dyspnoea lasting 2-5 hrs because of release of IL & TNF
II. Long term toxicity:
 Nephrotoxicity: Azotemia,
 Hypokalemia, acidosis, ↓ GFR
 anemia
III. CNS toxicity : intrathecal administration, headache,
vomiting, nerve palsies
IV. Hepatotoxicity rarely

38. III- OTHER ANTIFUNGAL DRUGS
38
 Flucytosine
 Prodrug, pyrimidine analog, antimetabolite
 Converted to 5-fluorouracil (5-FU)
 Human cells cant convert it to 5FU

39. 39
 Flucytosine
 Mechanism of action
 Flucytosine is actively transported into
fungal cells and is converted to the uracil
form 5-fluorouracil (5-FU) which inhibits
nucleic acid synthesis. Human cells lack the
ability to convert large amounts of
flucytosine into 5-FU.

41. Flucytosine
41
 Uses
 Used in combination with other antifungal agents (because
of rapid development of resistance) to treat Severe systemic
fungal infections.
 Adverse effects
 Flucytosine is relatively nontoxic
1. Depression of bone marrow at high doses
2. Hair loss.

42.  Griseofulvin
42
 Pharmacokinetics:
 Oral administration, irregular absorption, increased
by fatty food and microfine particles
 Gets conc in keratinized tissue
 Metabolized in liver, excreted in urine
 t1/2=24 hrs

43.  Griseofulvin
43
 Mechanism of action
 Griseofulvin binds to microtubules and
prevents spindle formation and mitosis
in fungi.
 It is fungistatic and requires long
duration of therapy.
 The drug binds to keratin structures and
accumulates in skin, hair, and nails.

45. Griseofulvin
45
 Therapeutic uses
 used orally for long-term therapy of dermatophyte infections
of the hair and nail.
 Adverse effects
1. Hepatotoxicity (liver functions should be checked during
therapy)
2. Hypersensitivity reactions (skin rash)
3. CNS effects: confusion, fatigue, vertigo.

46.  Nystain
46
 Nystatin is polyene macrolide very similar in kinetics and
mechanism to amphotericin B.
 It is too toxic for parenteral administration and is used only
topically.
 It is active mainly against Candida, and is used topically for
oralpharyngeal and vaginal candidiasis.

47.  Caspofungin
47
 It is large cyclic peptide that disrupts the fungal cell wall
resulting in cell death.
 Used by i.v. route for therapy in
i. Severe invasive aspergillosis
ii. Esophageal candidiasis who failed to respond to
amphotericin B (second line drug).

49. Ciclopirox
49
 Broad-spectrum antifungal effective against
dermatophytes and yeasts.
 Mechanism is unclear. (Has high affinity for trivalent
metal cations which inhibit essential co-factors in
enzymes).
 Used topically for skin and nail infections.

50. Terbinafine
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 Act by inhibiting squalene epoxidase, thereby
blocking the biosynthesis of ergosterol, an essential
component of the fungal cell membrane.
 Accumulation of toxic amounts of squalene results in
increased membrane permeability and death of the
fungal cell.
 The drug of choice for treating dermatophyte
onychomycoses
 better tolerated, requires a shorter duration of therapy,
and is more effective than either itraconazole or
griseofulvin

51. T H A N K Y O U !
A N Y Q U E S T I O N S ?