17/09/2014

LEARNING OBJECTIVES

Antifungal
Agents

To Explain
Antifungal Drug clasification
Pharmacological Aspect of Antifungal
Principles of clinical Use of Antifungal

Department of Pharmacology and Therapy

Introduction

Fungal infections
also called as mycoses

Both fungi and humans are eukaryots.

Difficult to find or design drugs that target fungi without

 Fungal

cell membranes have a unique

sterol, ergosterol, which replaces
cholesterol found in mammalian cell
membranes

affecting human cells. (side effects)

Slow onset infection

Long duration of therapy

Some of antifungal are fungistatic, while others are

fungicidal

Common fungal infections

Pityriasis versicolor
Candidiasis intertrigo,
paranychia stomatitis,
vulvovaginitis
tenia- corpis, cruris,
barbae, capatis, pedis,
manum, unguium

Histoplasmosis
coccidoiomycosis
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma

PATKI

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FUNGAL INFECTIONS
SYSTEMIC

HISTOPLASMOSIS

ASPERGILLOSIS

CRYPTOCOCCOSI

BLASTOMYCOSIS

MUCORMYCOSIS

CANDIDIASIS

LOCAL

DERMATOPHYTO.

SPOROTRICHIOSI.

ZYGOMYCOSIS

CHROMOMYCOSI.

RHINOSPOIDIOSIS

PATKI

systemic
/systemic

Systemic
/mucocutaneous

Amphotericin B.
Azoles
Flucytosine
Echinocandins

Antifungal drugs

AMPHOTERICIN B

Griseofulvin
Terbinafine

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

Topical
/mucocutaneous

Nystatine
Topical Azoles
Topical Allylamines

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

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Clinical use
Treatment of nearly all life threatening mycotic

infections.

For systemic disease:

Local:

Keratitis& corneal ulcers: drops, conjunctival irrigation,

Candiduria: bladder irrigation

Fungal arthritis: local injection

Side effects

Infusion related

slow IV

Liposomal Amphotericin B

Cumulative toxicity

Fever & chills,

Nephrotoxicity

New lipid formulations

Dyspnea,

K & Mg wasting

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.

Nausea &vomiting,
Hypotension,
Convulsions

Anemia
(erythropoietin)

To reduce the severity of the infusion-related

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

KEY POINTS

AMB is not absorbed enterally; hence can be

given orally for intestinal candidiasis.

FLUCYTOSINE (5(5-FC)

Pyrimidine antimetabolite, narrow-spectrum

fungistatic

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)

Water soluble
Oral only,

Poor protein binding

CSF (Cerebro Spinale Fluid) conc. 75% serum
conc.

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Flucytosine is

taken up by fungal cells via the

enzyme cytosine permease.

5-FC
(outside)

5-FC
(inside)

5-FU
(inside)
Inhibits
thymidylate
synthase

Cytosine
permease
enzyme

Inhibits
DNA &
RNA
synthesis

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.

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
Imidazoles

Ketoconazole
Miconazole
Clotrimazole

Inhibition of fungal
cytochrome P450
enzymes

Azoles
Triazoles

Itraconazole
Fluconazole
Voriconazole
Posaconazole

Reduction of
ergosterol
synthesis

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Clinical Use
Candida,
Cryptococcus,
Blastomyces,
Histoplasma,
Coccidiodes ,
Dermatophytes

KETOCONAZOLE
Adverse Effects

The first oral azole introduced into clinical use.

It is less selective for fungal P450 than are the newer

Relatively nontoxic.
Minor GI upset
Abnormalities in liver enzymes
(inhibit cytochrome P450 enzymes)
Very rarely, clinical hepatitis

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
Broad-spectrum antifungal with fungistatic action
Inhibits fungal ergosterol synthesis like other azoles

FLUCONAZOLE
Broad-spectrum Fungicidal drug;
It is also somewhat effective against some Grampositive & anaerobic bacteria

 Drug absorption is increased by food and by low

gastric ph.

Of the orally administered fluconazole 94% is

absorbed;

Penetration of drug in brain & CSF is poor.

 Much more selective than ketoconazole

Penetration in brain & CSF is good, hence used for

cryptococcal meningitis

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Posaconazole

ECHINOCANDINS

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
The newest class of antifungal .
Active against candida and
aspergillus, but not c neoformans or

Caspofungin
Micafungin
Anidulafungin

Mechanism of Action

Inhibit the
synthesis of B
glucan in the
fungal cell wall

the agents of zygomycosis and

mucormycosis.

Disruption of the
fungal cell wall and
cell death.
death

Adverse Effects
Extremely


well tolerated,

Minor GI side effects

Flushing


Elevated liver enzymes (caspofungin

+ cyclosporine).
Histamine

release during IV infusion.

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GRISEOFULVIN
 Very

Systemic antifungal drugs for

Mucocutaneous infections

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

Terbinafine

reaction

photosensitivity

Hepatitis

Teratogenesis

It interferes with
ergosterol biosynthesis
by:

Inhibiting the fungal

enzyme squalene
epoxidase
Accumulation of the
sterol squalene,

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.

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Adverse effects

Topical antifungal therapy

Rare, mild, self-limiting

GI upset
Rash
Pruritis
Headache.

TOPICAL ALLYLAMINES

TOPICAL AZOLES

Only used topically: creams, ointments,

Clotrimazole , Miconazole;

suppositories, and other

Vulvovaginal candidiasis, oral thrush ,

dermatophytic infections, including tinea corporis,

Acts as amphotericin B

tinea pedis, and tinea cruris.

It is not absorbed , unpleasant taste.

Local candidal infections, oropharyngeal
thrush, vaginal candidiasis.

Terbinafine and Naftifine

NYSTATIN
TOPICAL AZOLES
Clotrimazole , Miconazole

NYSTATIN

adverse effects are rare.

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

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ANTIFUNGAL DRUGS
DRUG
Amphotericin B

ACTION
Disrupts plasma
membrane of
fungal cells,
greater affinity
for ergosterol

Nystatin

Itraconazole

CLINICAL USE

UNDESIRABLE
EFFECTS

PHARMACOKINETICS

NOTES

DOC: systemic
fungal infections,
fungal meningitis
& fungal urinary
tract infections

Poor therapeutic
index (toxic at
therapeutic dose).
Fever & chills,
nephrotoxicity,
nausea, headache,
thrombophlebitis,
anemia,
hepatotoxicity,
cardiotoxicity

Slow IV for systemic

infections; intrathecal for
meningitis, bladder
irrigation for cystitis. No
need to reduce dose with
renal dysfunction.

CBC, urinalysis,
liver enzymes,
BUN, Crea, &
electrolytes
should be
checked before
and during tx

DOC: Intestinal
candidiasis or
oral thrush

Few adverse
effects

PO. Negligible absorption,

fecal excretion

Clotrimazole

Aspergillosis,
histoplasmosis,
coccidiomycosis,
sporotrichosis,
paracoccidiomyc
osis, tinea or
candidal
infections

unknown

Miconazole

Ketoconazole

Impairs
synthesis pf
ergosterol

DOC: P.
brasiliensis,
thrush, chronic
mucocutaneous
candidiasis,
dermatophytes

Nausea, diarrhea,
headaches, rsh,
dizziness, fatal
hepatic necrosis,
gynecomastia.
Risk of cardiac
arrhythmia with
Terfenadine

PO. Acid pH required for

dissolution. Absorption
decreased by food,
antacids, cimetidine

Follow LFTs.
Stop during
signs of liver
abnormalities

Fluconazole

Inhibits fungal
cytochrome
P450. Damages
plasma
membrane by
inhibiting sterol
demethylation

Systemic
histoplasmosis,
blastomycosis,
coccidiomycosis
or sporotrichosis.
Opportunistic
cryptococcosis,
candidiasis,
candidal thrush,
vaginitis,
esophagitis

Nausea,
headache, rash,
vomiting, diarrhea

PO/IV. Long half life.

Excellent penetration of
CSF, eye, urine. Hepatic
metabolism

No effect on
testosterone
synthesis.

Nausea, edema,
hepatitis. No
gynecomastia or
breast pain. Risk of
fatal cardiac
arrhythmias w/
terfenadine

DOC: candida
dermatophyte
infections of the
skin
Vaginal
candidiasis,
severe systemic
fungal infections

PO. Requires acidic

environment for
absorption

No effect on
testosterone
synthesis

topical

Phlebitis, pruritus,
nausea, fever, rash,
vomiting

Vaginal
suppositories/
topical/IV

Leucopenia, nausea,
diarrhea, Inc LFTs,
bone marrow
depression

Easily penetrates
CNS. Renal
excretion

Fungal
resistance
develops

Flucytosine

Deaminated to 5FU by the fungus.

Incorporated into
RNA. Metabolized
to 5-FdURD w/c
inhibits thymidilate
synthetase

Griseofulvin

Interferes w/
synthesis &
polymerization of
nucleic acids

Dermatophytes
of hair, skin, &
nails. Up to 6
months tx may
be required

Headaches, GI upset,
dec memory &
judgement,
leucopenia,
teratogenic

PO. Water insoluble,

powder absorbed
fairly well,
administration w/
fatty meal aids
absorption

Contraindicated
w/ pregnant
women. Drug
binds to keratin
of growing
tissues

Terbinafine

Inhibits squalene
epoxidase that
converts squalene
to ergosterol in
fungi

Toenail infection
due to
trichophyton
species

Neutropenia, skin
infections, ophthalmic
toxicity

PO. Long half life.

Good tissue
penetration

Monitor blood
counts

See u