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k4 - Antifungal Drugs
k4 - Antifungal Drugs
k4 - Antifungal Drugs
LEARNING OBJECTIVES
Antifungal
Agents
To Explain
Antifungal Drug clasification
Pharmacological Aspect of Antifungal
Principles of clinical Use of Antifungal
Introduction
Fungal
Pityriasis versicolor
Candidiasis intertrigo,
paranychia stomatitis,
vulvovaginitis
tenia- corpis, cruris,
barbae, capatis, pedis,
manum, unguium
Histoplasmosis
coccidoiomycosis
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma
PATKI
17/09/2014
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
Nystatine
Topical Azoles
Topical Allylamines
Mechanism of Action
MECHANISM OF ACTION
17/09/2014
Clinical use
Treatment of nearly all life threatening mycotic
infections.
Local:
Side effects
Infusion related
slow IV
Liposomal Amphotericin B
Cumulative toxicity
Nephrotoxicity
Dyspnea,
K & Mg wasting
Nausea &vomiting,
Hypotension,
Convulsions
Anemia
(erythropoietin)
KEY POINTS
FLUCYTOSINE (5(5-FC)
Water soluble
Oral only,
Poor protein binding
CSF (Cerebro Spinale Fluid) conc. 75% serum
conc.
17/09/2014
Flucytosine is
5-FC
(inside)
5-FU
(inside)
Inhibits
thymidylate
synthase
Cytosine
permease
enzyme
Inhibits
DNA &
RNA
synthesis
It
Adverse Effects
Bone
marrow
toxicity
with
anemia,
Mechanism of Action
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Inhibition of fungal
cytochrome P450
enzymes
Azoles
Triazoles
Itraconazole
Fluconazole
Voriconazole
Posaconazole
Reduction of
ergosterol
synthesis
17/09/2014
Clinical Use
Candida,
Cryptococcus,
Blastomyces,
Histoplasma,
Coccidiodes ,
Dermatophytes
KETOCONAZOLE
Adverse Effects
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
17/09/2014
Posaconazole
ECHINOCANDINS
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
Disruption of the
fungal cell wall and
cell death.
death
Adverse Effects
Extremely
well tolerated,
Flushing
+ cyclosporine).
Histamine
17/09/2014
GRISEOFULVIN
Very
insoluble, fungistatic
Derived from a species of penicillium.
Adverse effects
Allergic
Terbinafine
reaction
photosensitivity
Hepatitis
Teratogenesis
It interferes with
ergosterol biosynthesis
by:
Synthetic allylamine.
Orally Active.
Keratophilic , fungicidal.
17/09/2014
Adverse effects
TOPICAL ALLYLAMINES
TOPICAL AZOLES
Clotrimazole , Miconazole;
Acts as amphotericin B
NYSTATIN
TOPICAL AZOLES
Clotrimazole , Miconazole
NYSTATIN
TOPICAL ALLYLAMINES
17/09/2014
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
CBC, urinalysis,
liver enzymes,
BUN, Crea, &
electrolytes
should be
checked before
and during tx
DOC: Intestinal
candidiasis or
oral thrush
Few adverse
effects
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
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
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
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
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
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
Monitor blood
counts
See u