Anti-Fungal Drugs

Dr. Sameh Ahmad Muhamad abdelghany

Lecturer Of Clinical Pharmacology
Mansura Faculty of medicine
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.
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Lecture outline

1 4 Polyene Macrolides
Introduction
antifungals

2 Classification Of 5 Other antifungal drugs

Antifungals

3
Azoles

3
INTRODUCTION
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.

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FUNGI
 Fungi may be classified as
 Yeasts: Blastomyces, candida, histoplasma,
coccidioides,cryptococcus.
 Moulds: Aspergillus spp. , Dermatophytes

 Clinically classified as:

 Superficial mycosis
 Deep (systemic) mycosis
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FUNGI

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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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Types of fungal infections

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). 10
Types of fungal infections

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

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Types of fungal infections

II. Systemic mycoses:

 are fungal infections affecting
internal organs.
 It occurs in immunocompromized
patients e.g. cryptococcosis, and
aspergillosis (lung).

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CLASSIFICATION OF
ANTIFUNGALS
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

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Classification of antifungal drugs

I. Drugs for mucocutaneous infections:

i. Systemic drugs
 Azoles: Fluconazole, Itraconazole, Voriconazole.
 Griseofulvin
 Terbinafine

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

II. Drugs for Systemic infections: :

 Azoles: Fluconazole, Itraconazole, Voriconazole.
 Amphotericin-B
 Flucytosine
 Caspofungin

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Classification based on mechanism of
action
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
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Classification based on structure

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

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Classification based on structure

 ALLYLAMINES
 Terbinafine, butenafine
 ECHINOCANDINS
 Caspofungin, anidulafungin, micafungin
 OTHER TOPICAL AGENTS
 Tolnaftate, Undecyclinic acid, benzoic acid

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I- Azoles
 Chemistr y

 Ketoconazole, Miconazole, Fluconazole, Itraconazole,

Voriconazole

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

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I- Azoles
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
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Azoles
 Phar macokinetics
 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

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Azoles
 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.
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27
Azoles
 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.
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Azoles
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.
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Azoles
 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. 30
II- Amphotericin-B
 Chemistry

 Obtained from Streptomyces Nodosus

 Amphoteric in nature

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Amphotericin-B
 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.
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Amphotericin-B
 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.

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Amphotericin-B
 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.

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Amphotericin-B
 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.

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

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 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.

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Flucytosine
 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.
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 Griseofulvin
 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

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 Griseofulvin
 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.
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Griseofulvin
 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.
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 Nystain
 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.

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 Caspofungin
 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).

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Ciclopirox
 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.

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Terbinafine
 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
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griseofulvin
THANK YOU!
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