Antifungal

Agents
Laboratorium Farmakologi dan Terapi
Fakultas Kedokteran
Universitas Jenderal Soedirman
LEARNING OBJECTIVES
● To Explain
◦ Antifungal Drug clasification
◦ Pharmacological Aspect of Antifungal
◦ Principles of clinical Use of Antifungal
 Introduction
● Fungal infections → also called as mycoses
● Both fungi and humans are eukaryots.
● Difficult to find or design drugs that target fungi without
affecting human cells. (side effects)
● Slow onset infection

● Long duration of therapy

● Some of antifungal are fungistatic, while others are
fungicidal
➢ Fungal cell membranes have a unique
sterol,  ergosterol, which  replaces
cholesterol found in mammalian cell
membranes
 Common fungal infections

● Pityriasis versicolor ● Histoplasmosis

● Candidiasis - ● coccidoiomycosis
intertrigo, ● blastomycosis
paranychia ● cryptococcosis
stomatitis,
● aspergillosis
vulvovaginitis
● mucormicosis
● tenia- corpis, cruris,
barbae, capatis, ● mycetoma
pedis,
manum, unguium
PATKI 6
 FUNGAL INFECTIONS

SYSTEMIC LOCAL
● HISTOPLASMOSIS ● DERMATOPHYTO.
● ASPERGILLOSIS ● SPOROTRICHIOSI.
● CRYPTOCOCCOSI ● ZYGOMYCOSIS
● BLASTOMYCOSIS ● CHROMOMYCOSI.
● MUCORMYCOSIS ● RHINOSPOIDIOSIS
● CANDIDIASIS

PATKI 7
Antifungal drugs
AMPHOTERICIN B

● Broad-spectrum polyene macrolide antibiotic is

the most potent antifungal agent for systemic
mycosis, in clinical use since 1960
● Fungicidal drug at higher concentrations & static
at lower levels.
Produced by Streptomyses nodosum
● CSF conc.= 2-3 % of blood conc.
● Highest concentrations in liver, spleen, bone
marrow with less in kidneys and lungs.
Mechanism of Action
 MECHANISM OF ACTION

● High affinity for fungal ergosterol, forms

“micropore” in fungal cell membrane through which
ions, amino acids, & other water soluble substances
move out.
● Markedly increases cell permeability.
● Cholestrol, present in host cell membranes, closely
resembles fungal ergosterol & thus explains the
high toxicity in humans
Clinical use
● Treatment of nearly all life threatening mycotic
infections.

● For systemic disease: slow IV

o Local:

o Keratitis& corneal ulcers: drops, conjunctival irrigation,

o Candiduria: bladder irrigation

o Fungal arthritis: local injection

Side effects

● Infusion related ● Cumulative toxicity

Fever & chills,
Nephrotoxicity
Dyspnea, K & Mg wasting
Nausea &vomiting, Anemia
Hypotension,
(↓erythropoietin)
Convulsions

● To reduce the severity of the infusion-related

reactions, pretreatment with an antipyretic
(acetaminophen), antihistamines, and
antiemetics may be given.
Liposomal Amphotericin B

● New lipid formulations

● Amphotericin B is incorporated into lipid
formulations to reduce toxicity & enhance
efficacy. This allows higher dose to be used
without increasing the toxicity.
● Much more expensive than ordinary AMB.
KEY POINTS

● AMB is not absorbed enterally; hence can be

given orally for intestinal candidiasis.

● Drug concentration achieved in infected skin is

very low, & hence ineffective against superficial
fungal infections.

● Penetration in brain & CSF is poor (but extremely

effective in fungal meningitis when combined
with 5-FC (flucitocin))
 FLUCYTOSINE (5-FC)
● Pyrimidine antimetabolite, narrow-spectrum
fungistatic

● Water soluble
• Oral only,
● Poor protein binding
● CSF (Cerebro Spinale Fluid) conc. ≈ 75%
serum conc.
• Flucytosine is taken up by fungal cells via
the enzyme cytosine permease.
• It is converted intracellularly first to 5-FU
and then to 5-fluorodeoxyuridine
monophosphate (FdUMP) and
fluorouridine triphosphate (FUTP), which
inhibit DNA and RNA synthesis,
respectively.
Why 
the d
ru g doe
s not
 a ct on
 hum
an ce
lls?

Human cel
ls are
unable to c
onvert the
parent dru
g to its
active met
abolites.
 Adverse Effects
• Bone marrow toxicity with anemia,
leukopenia, thrombocytopenia,
(Mammalian bone marrow cell have the
capacity to convert 5-FC to 5-FU)
• GI disturbances

● Mild & reversible liver dysfunction

Mechanism of Action
Clinical Use
Candida,
Cryptococcus,
Blastomyces,
 Histoplasma,
 Coccidiodes ,
Dermatophytes
 Adverse Effects
Relatively nontoxic.
Minor GI upset
Abnormalities in liver enzymes
(inhibit cytochrome P450 enzymes)
Very rarely, clinical hepatitis
 KETOCONAZOLE
• The first oral azole introduced into clinical use.
• It is less selective for fungal P450 than are the newer
azoles.

• Absorption variable (better in acidic medium)
• Penetration in brain & CSF is poor
• In high doses inhibits adrenocortical steroids and
testosterone synthesis, resulting in gynecomastia in
some males.
 ITRACONAZOLE

❑ Broad­spectrum antifungal with fungistatic action
❑ Inhibits fungal ergosterol synthesis like other azoles
❑    Drug absorption is increased by food and by low
gastric ph.
❑ Penetration of drug in brain & CSF is poor.
❑   Much more selective than ketoconazole
 FLUCONAZOLE
❑ Broad­spectrum Fungicidal drug;
❑ It is also somewhat effective against some Gram­
positive & anaerobic bacteria

❑ Of the orally administered fluconazole 94% is
absorbed;

❑ Penetration in brain & CSF is good, hence used for
cryptococcal meningitis
 Posaconazole
❑ The newest triazole
❑ It is the broadest spectrum member of the azole family.
❑  It is the only azole with significant activity against the
agents of zygomycosis and mucormycosis.
ECHINOCANDINS

Caspofungin
 Micafungin
Anidulafungin  
 ECHINOCANDINS
❑ The newest class of antifungal .
❑ Active against candida and
aspergillus, but not c neoformans or
the agents of zygomycosis and
mucormycosis.
Mechanism of Action
Adverse Effects
• Extremely well tolerated,
•  Minor GI side effects
• Flushing
•  Elevated liver enzymes
(caspofungin + cyclosporine).
• Histamine release during IV infusion.
Systemic antifungal drugs for

Mucocutaneous infections
 GRISEOFULVIN
• Very insoluble, fungistatic
•  Derived from a species of penicillium.
•  Better absorption when given with fatty foods.

● It is deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection.
● Interferes with spindle formation in dividing cells and
therefore with mitosis
Adverse effects

● Allergic reaction
● photosensitivity
● Hepatitis
● Teratogenesis
Terbinafine

● Synthetic allylamine.

● Orally Active.

● Dermatophytoses, especially onychomycosis .

● Keratophilic , fungicidal.
● Like the azole drugs, it interferes with
ergosterol biosynthesis, but rather than
interacting with the P450 system,
terbinafine inhibits the fungal enzyme
squalene epoxidase. This leads to the
accumulation of the sterol squalene, which
is toxic to the organism.
Adverse effects

Rare, mild, self­limiting

GI upset
Rash
Pruritis
Headache.
Topical antifungal therapy
● NYSTATIN
● TOPICAL AZOLES
◦ Clotrimazole , Miconazole
● TOPICAL ALLYLAMINES
◦ Terbinafine and Naftifine
●
 NYSTATIN
● Only used topically: creams, ointments,
suppositories, and other
● Acts as amphotericin B
●  It is not absorbed , unpleasant taste.
● Local candidal infections,
oropharyngeal thrush, vaginal
candidiasis.
● adverse effects are rare.
 TOPICAL AZOLES
● Clotrimazole , Miconazole;
● Vulvovaginal candidiasis, oral thrush ,
dermatophytic infections, including tinea
corporis, tinea pedis, and tinea cruris.
● Absorption is negligible, and adverse effects are
rare.
● Topical and shampoo forms of ketoconazole for
seborrheic dermatitis and pityriasis versicolor.
 TOPICAL ALLYLAMINES
● Terbinafine and Naftifine
● Both are effective for treatment of tinea
cruris and tinea corporis.
● Inhibits the squalene epoxidase, leading to
accumulation of intrcellular squalene & deficient
ergosterol synthesis with subseqent fungal cell
death.
● Terbinafine concentrates in skin and
especially at nail beds, making it quite
useful for fungal infection of nails
 ANTIFUNGAL DRUGS

DRUG ACTION CLINICAL USE UNDESIRABLE PHARMACOKINETICS NOTES

EFFECTS
Amphotericin B Disrupts plasma DOC: systemic Poor therapeutic Slow IV for systemic CBC,
membrane of fungal infections, index (toxic at infections; intrathecal for urinalysis,
fungal cells, fungal therapeutic dose). meningitis, bladder liver enzymes,
greater affinity meningitis & Fever & chills, irrigation for cystitis. No BUN, Crea, &
for ergosterol fungal urinary nephrotoxicity, need to reduce dose with electrolytes
tract infections nausea, headache, renal dysfunction. should be
thrombophlebitis, checked
anemia, before and
hepatotoxicity, during tx
cardiotoxicity

Nystatin DOC: Intestinal Few adverse PO. Negligible absorption, .

candidiasis or effects fecal excretion
oral thrush

Ketoconazole Impairs DOC: P. Nausea, diarrhea, PO. Acid pH required for Follow LFTs.
synthesis pf brasiliensis, headaches, rsh, dissolution. Absorption Stop during
ergosterol thrush, chronic dizziness, fatal decreased by food, signs of liver
mucocutaneous hepatic necrosis, antacids, cimetidine abnormalities
candidiasis, gynecomastia.
dermatophytes Risk of cardiac
arrhythmia with
Terfenadine

Fluconazole Inhibits fungal Systemic Nausea, PO/IV. Long half life. No effect on
cytochrome histoplasmosis, headache, rash, Excellent penetration of testosterone
P450. Damages blastomycosis, vomiting, diarrhea CSF, eye, urine. Hepatic synthesis.
plasma coccidiomycosis metabolism
membrane by or
inhibiting sterol sporotrichosis.
demethylation Opportunistic
cryptococcosis,
candidiasis,
candidal thrush,
vaginitis,
esophagitis
Itraconazole Aspergillosis, Nausea, edema, PO. Requires acidic No effect on
histoplasmosis, hepatitis. No environment for testosterone
coccidiomycosis, gynecomastia or absorption synthesis
sporotrichosis, breast pain. Risk of
paracoccidiomyc fatal cardiac
osis, tinea or arrhythmias w/
candidal terfenadine
infections

Clotrimazole unknown DOC: candida topical

dermatophyte
infections of the
skin

Miconazole Vaginal Phlebitis, pruritus, Vaginal

candidiasis, nausea, fever, rash, suppositories/
severe systemic vomiting topical/IV
fungal infections

Flucytosine Deaminated to 5- Leucopenia, nausea, Easily penetrates Fungal

FU by the fungus. diarrhea, Inc LFTs, CNS. Renal resistance
Incorporated into bone marrow excretion develops
RNA. Metabolized depression
to 5-FdURD w/c
inhibits
thymidilate
synthetase

Griseofulvin Interferes w/ Dermatophytes Headaches, GI upset, PO. Water insoluble, Contraindicated

synthesis & of hair, skin, & dec memory & powder absorbed w/ pregnant
polymerization of nails. Up to 6 judgement, fairly well, women. Drug
nucleic acids months tx may leucopenia, administration w/ binds to keratin
be required teratogenic fatty meal aids of growing
absorption tissues

Terbinafine Inhibits squalene Toenail Neutropenia, skin PO. Long half life. Monitor blood
epoxidase that infection due to infections, ophthalmic Good tissue counts
converts squalene trichophyton toxicity penetration
to ergosterol in species
fungi
See u…