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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. AzizDepartment of Pharmacology
School of Medicine University of Sulaimani
FUNGAL INFECTIONS = MYCOSES
Opportunistic or primary
Systemic 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 & topicalSystemic & topical
some are fungistatic, some are fungistatic,
while others are fungicidalwhile others are fungicidal
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.
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.
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
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
MECHANISM OF ACTION
CLINICAL USEBROAD 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
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, self-limiting
GI upset Rash
PruritisHeadache.
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 and Naftifine
Both 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
Thank you