Transcript Antifungal Agents

Recommended text books
Basic and Clinical pharmacology, 10th or 11th
edition, B.G.Katzung, LANGE medical book.
Lippincott´s ilustrated reviews: Pharmacology 3rd
edition, R.A.Harvey, Champe P.C., R.D. Howland,
M.J. Mycek, Lippincott-Raven,.
Pharmacology, 6th edition, H.P.Rang, M.M. Dále,
J.M. Ritter, Churchill Livingstone, 2007.
Antifungal
Agents
Dr. Roshna S. Aziz
Department of Pharmacology
School of Medicine
University of Sulaimani
Widespectrum
antibiotics
surgery
Increase
risk
Immunosuppressant
agents &
chemotherapy
AIDS
FUNGAL INFECTIONS = MYCOSES
 Opportunistic
 Systemic
or primary
or local
 Slow
onset
 Long
duration of therapy
 Difficult
to diagnose & eradicate
 Symptoms
vary from cosmetic to life
threatening
Antifungal drugs
 Work
by exploiting differences between
mammalian and fungal cells to kill the fungal
organism without dangerous effects on the host.
 Both
fungi and humans are eukaryots.
 Difficult
to find or design drugs that target
fungi without affecting human cells. (side
effects)
 Fungal
cell membranes have a unique
sterol, ergosterol, which replaces
cholesterol found in mammalian cell
membranes
ANTIFUNGAL DRUGS
Systemic & topical
some are fungistatic,
while others are fungicidal
systemic
/systemic
• Amphotericin B.
• Azoles
• Flucytosine
• Echinocandins
Systemic
/mucocutaneous
• Griseofulvin
• Terbinafine
Topical
/mucocutaneous
• Nystatine
• Topical Azoles
• Topical Allylamines
SYSTEMIC ANTIFUNGAL
DRUGS
FOR SYSTEMIC INFECTIONS
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 of AMB 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
Fever & chills,
Dyspnea,
Nausea &vomiting,
Hypotension,
Convulsions


Cumulative toxicity
Nephrotoxicity
K & Mg wasting
Anemia
(↓erythropoietin)
To reduce the severity of the infusion-related reactions,
pretreatment with an antipyretic (acetaminophen),
antihistamines, and antiemetics may be given.
Amphotericin B
Amphotericin B
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)
FLUCYTOSINE (5-FC)
 Pyrimidine
antimetabolite, narrow-spectrum
fungistatic
 Water
soluble
• Oral only,
 Poor protein binding
 CSF conc. ≈ 75% serum conc.
•5-FC
(outside)
Cytosine
permease
enzyme
•5-FC
(inside)
•5-FU
(inside)
Inhibits
thymidylate
synthase
• Inhibits
DNA &
RNA
synthesis
 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.
Human cells are
unable to convert
the parent drug to
its active
metabolites.
Clinical use at present is confined to
combination therapy, either
with:

Amphotericin B for cryptococcal
meningitis , or

Itraconazole for
chromoblastomycosis
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
KEY POINTS
 Since
this is a narrow-spectrum
fungistatic, it is mainly used as an
adjuvant drug & not used as a sole
therapy.
 CSF
penetration is excellent, hence it is
combined with AMB in fungal meningitis.
AZOLES
Ketoconazole
Imidazoles
Miconazole
Clotrimazole
Azoles
Itraconazole
Triazoles
Fluconazole
Voriconazole
Posaconazole
MECHANISM OF ACTION
Inhibition of
fungal
cytochrome P450
enzymes
Reduction
of ergosterol
synthesis
CLINICAL USE
BROAD SPECTRUM OF ACTIVITY –
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
•(older, more toxic, replaced by itraconazole, but less costly)
•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
•Broad-spectrum antifungal with fungistatic action
•MOA: 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
Broad-spectrum 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
Inhibit the synthesis
of B glucan in the
fungal cell wall
Disruption of the
fungal cell wall
and cell death.
ADVERSE EFFECTS
 Extremely

well tolerated,
Minor GI side effects
 Flushing

Elevated liver enzymes
(caspofungin + cyclosporine).
Histamine
infusion.
release during IV
SYSTEMIC ANTIFUNGAL
FOR
MUCOCUTANEOUS
INFECTIONS
DRUGS
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
 Orally
allylamine.
Active.
 Dermatophytoses,

especially onychomycosis .
Keratophilic , fungicidal.
It interferes with
ergosterol biosynthesis
by:
Inhibiting the fungal
enzyme squalene
epoxidase
Accumulation of the
sterol squalene,
 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, self-limiting
GI upset
Rash
Pruritis
Headache.
Topical antifungal therapy
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
 Both
and Naftifine
are effective for treatment of tinea
cruris and tinea corporis.
 MOA:
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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