ADAMA GENERAL HOSPITAL AND

MEDICAL COLLEGE

5/15/2021 1
 OUT LINE
• In this Seminar presentation we will see
• Definition of fungi
• Different Antifungal Agents
• Classifications
• Summery
• Targets of Antifungal Agent
• MOA
• AE
• Clinical Uses
5/15/2021 2
 FUNGI

Also known as mycoses

Very large and diverse group of microorganisms
Of major two types: yeasts and molds.

5/15/2021 3
 MYCOTIC INFECTIONS:

 Cutaneous
 Subcutaneous
 Superficial
 Systemic:
 Can be life-threatening
 Usually occur in immunocompromised host.
5/15/2021 4
 ANTIFUNGAL AGENTS


Fungal infections have increased in incidence and severity in
recent years,
due to increased in the use of broad-spectrum antimicrobials
and the HIV epidemic.
The antifungal drugs fall into two groups:
A. antifungal antibiotics and
B.synthetic antifungals.

5/15/2021 5
 SUMMARY OF ANTIFUNGAL DRUGS.

1. In this topic We Discuss About Drugs for subcutaneous and systemic

mycoses such as:

• Voriconazole, Posaconazole, Micafungin,

• Fluconazole, Caspofungin, Anidula fungin,
• Ketoconazole, Iitraconazole, Flucytosine,
• Amphotericin B; And
5/15/2021 6
 SUMMARY CONTD,…

2. Drugs for cutaneous mycoses such that:

• Terconazole, Terbinafine ,Nystatin
• Miconazole, Griseofulvin, Econazole,
• Clotrimazole, Butoconazole (according to Lippincott´s Pharmacology, 2009)

5/15/2021 7
 TARGETS FOR ANTIFUNGAL AGENTS

• Generally these targets should be different from mammalians.

• Both human and fungi are eukaryotic, so not much difference could be found.

• The most important difference is the presence of cell wall for fungi that is not found in humans.

5/15/2021 8
 OTHER TARGETS ARE:

• Inhibitors of DNA synthesis.

• Disruption of mitotic spindle.
• Interfere with metabolism

5/15/2021 9
 OTHER TARGEST CNTND,…

Mammalians contain cholesterol while fungi posses

ergosterol.
The difference is in the side chain of ergosterol which is
more flat compared to cholesterol;
A difference that is responsible for providing selectivity for
the majority of antifungal agents.
Cholesterol Ergosterol

5/15/2021 10
 AMPHOTERICIN B

•  Amphotericin B: is poorly absorbed from the gastrointestinal tract.

• Oral amphotericin B is thus effective only on fungi within the lumen of the tract.
• The drug is widely distributed in tissues, but only 2-3% of the blood level is reached in CSF,
• thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.

5/15/2021 11
Amphotericin

5/15/2021 12
 MECHANISM OF ACTION:
• Amphotericin B binds to ergosterol (a cell
membrane sterol) and
• Alters the permeability of the cell by forming
amphotericin B-associated pores in the cell
membrane.
• The pore allows the leakage of intracellular ions
and macromolecules, eventually leading to cell
death. 5/15/2021 13
 ADVERSE EFFECTS:

• The toxicity of amphotericin B which may occur immediately or

delayed include
• fever,
• chills,
• muscle spasms,
• vomiting,
• headache,
5/15/2021 14
 ADVERSE EFF. CONTD,…

• hypotension (related to infusion),

• renal damage associated with decreased renal perfusion (a
reversible) and
• renal tubular injury (irreversible).
• Anaphylaxis,
• liver damage,
• anemia occurs infrequently
5/15/2021 15
 ANTIFUNGAL ACTIVITY:

• Amphotericin B is a broad-spectrum antifungal agent.

• It has activity against yeasts including;
 Candida albicans and Cryptococcus neoformans;
 molds,
 Aspergillus fumigatus.
• Clinical Use: Amphotericin B remains the drug of choice for
nearly all life-threatening mycotic infections .
5/15/2021 16
 ANTIFUNGAL ACTIVITY CONTD…
• Used as the initial induction regimen for serious
fungal infections such as
 immunosuppressed patients,
 severe fungal pneumonia, and
 cryptococcal meningitis with altered
mental status.
5/15/2021 17
 NYSTATIN

• Nystatin has similar structure with amphotericin B and

• has the same pore-forming mechanism of action.
• It is too toxic for systemic use and
• is only used topically.
• It is not absorbed from :
 skin,
 mucous membranes or
 the gastrointestinal tract.
5/15/2021 18
 CONTD,…

• Nystatin is active against most Candida species and

• is most commonly used for suppression of local candidal infections.
• Nystatin is used in the treatment of
 oropharyngeal thrush
 vaginal candidiasis and
 intertriginous candidal infections .
5/15/2021 19
 GRISEOFULVIN

• Griseofulvin is a fungistatic and

• used is in the treatment of dermatophytosis.
• Absorption is improved when it is given with fatty foods.
• Griseofulvin is deposited in newly forming skin where it
binds to keratin,
• protecting the skin from new infection.
5/15/2021 20
 GRISEOFULVIN CONTD,…

• It must be administered for 2-6 weeks for skin and hair

infections to allow the replacement of infected keratin by
the resistant structures.
• Nail infections may require therapy for months to allow
regrowth of the new protected nail and
• is often followed by relapse.
 Orally taken for superficial infections.
 Not used topically. 5/15/2021 21
 ADVERSE EFFECT OF GRISOFULVINE

• Adverse effects include an allergic syndrome much like

• serum sickness
• hepatitis and
• drug interactions with warfarin and phenobarbital.
• Griseofulvin has been largely replaced by newer antifungal
medications such as itraconazole and terbinafine.
5/15/2021 22
 SYNTHETIC ANTIFUNGAL AGENTS FLUCYTOSINE

• Flucytosine
• is related to fluorouracil (5-FU).
• Its spectrum of action is much narrower than that of
amphotericin B.
• It is well absorbed orally.
• It is poorly protein-bound and penetrates well into all body
fluid compartments including the CSF.
5/15/2021 23
 COND,…

• It is eliminated by glomerular filtration.

• Toxicity is more likely to occur in AIDS patients and in the
presence of renal insufficiency.
• Flucytosine is converted intracellularly first to 5-FU and
• then to 5-fluorodeoxyuridine monophosphate (F-dUMP) and
• fluorouridine triphosphate (FUTP), which inhibit DNA and
RNA synthesis, respectively.
5/15/2021 24
 CLINICAL USE:
• Active against;
• Cryptococcus neoformans,
• some Candida species and
• the dematiaceous molds that cause chromoblastomycosis.
• Clinical use at present is confined to combination therapy,
• either with amphotericin B for cryptococcal meningitis or
• with itraconazole for chromoblastomycosis.
5/15/2021 25
 ADVERSE EFFECTS:

• The adverse effects of flucytosine result from metabolism

(intestinal flora) to the toxic antineoplastic compound flucytosine.
• Bone marrow toxicity with
• anemia
• Leukopenia and
• thrombocytopenia are the most common adverse effects,
• with derangement of liver enzymes occurring less frequently.

5/15/2021 26
 AZOLES

• Are Clasified as Ergosterol Biosynthesis inhibitors

• Azoles are synthetic compounds that can be classified as imidazole and
triazoles.
• The imidazole consist of
• Ketoconazole
• Miconazole and
• Clotrimazole.
• The triazoles include
• Itraconazole and
• fluconazole. 5/15/2021 27
 CONTD,…
• The antifungal activity of azole drugs results from the
reduction of ergosterol synthesis by inhibition of fungal
cytochrome P450 enzymes.
• The specificity of azole drugs results from their greater
affinity for fungal than for human cytochrome P450 enzymes.
• Imidazole's exhibit a lesser degree of specificity than the
triazoles, accounting for their higher incidence of drug
interactions and side effects.
5/15/2021 28
 CONTD,…

• Azoles are active against many Candida species,

• Cryptococcus neoformans,
• the endemic mycoses (blastomycosis, coccidioidomycosis)
• the dermatophytes and,
• Aspergillus infections (itraconazole).

5/15/2021 29
 ADVERSE EFFECTS:

• The azoles are relatively nontoxic.

• The most common adverse reaction is minor
gastrointestinal upset. Most azoles cause
abnormalities in liver enzymes and,
• very rarely, clinical hepatitis.

5/15/2021 30
 IMIDAZOLES

1. Ketoconazole
• Ketoconazole is less selective for fungal P450 than are the fluconazole and itraconazole ( inhibit mammalian
cytochrome P450 enzymes ).
• Clinical use:
• it has limited use because of:
• the drug interactions
• endocrine side effects and
• of its narrow therapeutic range.

5/15/2021 31
 CLINICAL USE CONTD,..

• Oral formulation that is best absorbed at a low gastric pH.

• Ketoconazole is used in treatment of
• mucocutaneous candidiasis and
• nonmeningeal coccidioidomycosis.
• It is also used in the treatment of seborrheic dermatitis and
• pityriasis versicolor (Topical/shampoo).
5/15/2021 32
 ADVERSE EFFECTS:
• First, ketoconazole inhibition of human cytochrome
P450 enzymes interferes with biosynthesis of adrenal
and gonadal steroid hormones,
• producing significant endocrine effects such as:
• gynecomastia
• Infertility and
• menstrual irregularities.
5/15/2021 33
 ADVERSE EFFECTS CONTD,…

• Second, the interaction with P450 enzymes can alter

the metabolism of other drugs, leading to enhance
toxicity of those agents.
• eg. increased levels and enhanced arrhythmogenic
effects of the no sedating antihistamines, and
terfenadine.

5/15/2021 34
 CLOTRIMAZOLE AND MICONAZOLE

• Clotrimazole and miconazole :

• are available over-the-counter and
• are often used for vulvovaginal candidiasis.
• Oral clotrimazole troches are available for
treatment of oral thrush and
• are a pleasant-tasting alternative to nystatin.

5/15/2021 35
 CLOTRIMAZOLE AND MICONAZOLE CNTD,…

• In cream form, both agents are useful for dermatophytic

infections,including
• Tinea corporis,
• Tinea pedis and
• Tinea cruris.
• Absorption is negligible, and adverse effects are rare.
5/15/2021 36
 THANK YOU

•ULFAADHAA !
5/15/2021 37
5/15/2021 38