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Kalpana Eluri
Faculty of Medicine
UCSI University
Fungus
o
o
o
o
o
Also
known as mycoses
Broken
Yeasts
Single-cell fungi
Reproduce by budding
Very useful organisms
- Baking
- Alcoholic beverages
3
Molds
Multicellular
Characterized by long, branching
filaments called hyphae
Mycotoxicosis
Production of toxin
Mycetismus
Pre-formed toxin
Infection
Fungal Infections
Candida
Vaginal Candidiasis
Oral thrush
Athlete's foot
Tinea
Allergic bronchopulmonary
aspergillosis
6
Fungal infections
Classification
Superficial mycoses
Affect the skin, hair and nails
Subcutaneous mycoses
Affect the muscle and connective tissue
immediately below the skin
Allergic mycoses
Affect lungs or sinuses
(Patients may have chronic asthma,
sinusitis)
8
Pathogenic fungi
Candidiasis
Zygomycota
Aspergillosis
9
Immunocompromise
AIDS
Chronic disease
10
Azoles
- Imidazole: Ketoconazole, miconazole,
terconazole, clotrimazole, econazole
- Triazole: Fluconazole, itraconazole,
voriconazole
Allylamine
- Terbinafine
Others
- Griseofulvine & Flucytosine
11
griseofulvin disrupts
the mitotic spindle
nucleus
amphotericin and
nystatin form pores
in the cell membrane
flucytosine blocks
DNA synthesis
12
Amphotericin B
It is a polyene macrolide antibiotic
produced by Streptomyces nodosus
It is the drug of choice for lifethreatening fungal infections
MOA
Drug molecules bind to ergosterol in the
fungal cell membrane
It forms pores in the membrane
Electrolytes (especially potassium) and
smaller molecules leak from the cell
membrane resulting in cell death
13
Antifungal
spectrum
Drug is fungicidal
or fungistatic
depending on the
organism and the
concentration of
the drug.
Effective against
Candida albicans,
Histoplasma
capsulatum,
Cryptococcus
neoformans,
blastomyces
14
Pharmacokinetics
16
Adverse Effects
- Convulsions
- Thrombophlebiti
s
- Serious
neurological
problems
Adverse Effects
Kidney failure:
Adequate hydration can decrease the severity
Hypotension:
Shock like fall in blood pressure
accompanied by hypokalemia occur. Can
be treated with potassium
supplimentation.
Anemia:
Reversible suppression of erythrocyte production
occur
19
Drug interactions
Amphotericin
B
administered
together
with
Aminoglycosides/cyclosporine/penta
midine
Azotemia is exacerbated. Nephrotoxicity
(Decrease in renal tubular function and
glomerular filtration rate)
Amphotericin
B
administered
together with Digitalis
A shock-like fall in blood pressure
will occur due to hypokalemia
20
Drug interactions
Amphotericin B administered together
with Zidovudine
Anemia caused due to suppression of
erythrocyte production
Amphotericin B administered together
with Heparin
Will cause thrombophlebitis
21
Therapeutic uses
The drug of choice for
Cryptococcal meningitis
Mucormycosis (zygomycosis)
Invasive fungal infection, not responding
to other therapy
22
Nystatin
It is a polyene macrolide antibiotic
Mechanism of action, bacterial resistance
mechanism are same as Amphotericin B
It is used for topical treatment of Candida
infections.
Not used internally because of systemic
toxicity.
23
Ketoconazole
Azoles are fungistatic
Mechanism of action:
Inhibit C-14 -demethylase. Thus
blocks the demethylation of
lanosterol to ergosterol
This inhibition disrupts the
membrane structure and function
thereby inhibits fungal cell growth.
24
25
Ketoconazole
It is a second-line drug for the treatment
of mucocutaneous candidiasis
Fungal Resistant mechanism
Mutations in the C-14 -demethylase
gene which causes decreased drug
binding
Some strains have developed the ability
to pump the drug out of the cell
26
Ketoconazole-Pharmacokinetics
It administered orally
Drug is well absorbed in acidic pH
Extensively bound to plasma proteins
Metabolized by liver enzymes
Eliminated through biliary route
27
Ketoconazole-Adverse effects
Allergy
Nausea, vomiting and anorexia
Endocrine effects : gynacomastia,
decreased libido, impotence and
menstrual irregularities
Hepatitis in 10% patients
28
Ketoconazole-Drug Interactions
When Ketoconazole administered
together with antacids/H2-receptor
blockers/proton-pump inhibitors
Usually Ketoconazole is dissolved and
absorbed in acidic pH. These drugs impair the
absorption of ketoconazole
Ketoconazole-Drug Interactions
Ketoconazole administered together with
cyclosporine/phenytoin/tolbutamide and
warfarin
Ketoconazole inhibits the CYP 450 enzyme
production. Potentiates the toxicity of the
above drugs
Ketoconazole-Contraindications
Ketoconazole is contraindicated
in pregnancy
Ketoconazole should not be
administered together with
Amphotericin B
31
Ketoconazole-Therapeutic uses
Fungal pneumonia
Cryptococcal meningitis
Sepsis syndrome due to fungal
infection
Mycotic corneal ulcers
Keratitis
Fungal arthritis
32
Terbinafine
It is more effective than itraconazole
and griseofulvin. Drug is fungicidal
Mechanism of action
Inhibits
fungal
squaline
epoxidase
Thereby decreasing the synthesis
of ergosterol
Accumulation of toxic amounts of
squaline results fungal cell death
33
34
Antifungal spectrum
Effective on candida albicans
Pharmacokinetics
Orally active. Bioavailability is 40% due
to first-pass metabolism
More than 99% is bound to proteins
It is deposited in the skin, nails and fat
It is accumulated in breast milk
Extensively metabolized and eliminated
through renal route
35
ADR
Diarrhea, dyspepsia and nausea
Taste and visual distrubances
Rarely
cause
hepatotoxicity
neutropenia
and
Drug interactions
Rifampin enhance the metabolism of
terbinafine. Therapeutic activity of
terbinafine decreases.
Cimetidine inhibits the metabolism of
terbinafine and increase the therapeutic
efficacy.
Therapeutic uses
Dermatophytic infections
Onchomycoses
36
Griseofulvine
Mechanism of action
It
accumulates
in
newly
synthesized, keratin containing
tissue.
It cause disruption of the
mitotic spindle and inhibits
fungal mitosis
It is replaced by terbinafine
It is fungistatic
Ultracrystalline
preparations
absorbed from GIT
Absorption enhanced by high-fat
37
38
ADR
Porphyria (insufficient production of heme and
produce porphyrin)
Drug interactions
Griseofulvin administered
with anticoagulants
together
Increase
the
metabolism
of
anticoagulants. Therapeutic efficacy of
anticoagulants will be reduced
Flucytosine
MOA
Flucytosine enters fungal cells via
cytosine-specific-permease.
There Flucytosine is converted to 5fluorodeoxyuridine 5-monophosphate
(5-FdUMP)
This false neucleotide inhibits
thymidine synthase
Drug inhibits thymidine synthesis which
is required for DNA synthesis
40
41
Pharmacokinetics
Well absorbed through oral route.
Well distributed. Enters into CSF
Metabolized by liver enzymes
Antifungal spectrum
It is fungistatic drug
Effective for cryptococcosis,
chromoblastomycosis
42
ADR
Neutropenia, thrompbocytopenia
Bone marrow depression occasionally
Hepatotoxicity
Nausea, vomiting and diarrhea
Severe enterocolitis
43