Antifungal drugs

Kalpana Eluri

Faculty of Medicine
UCSI University

Fungus
o
o
o
o
o

Eucaryotic a true nucleus

Do not contain chlorophyll
Have cell walls
Produce filamentous structures
Produce spores
- 100,000-200,000 species
- About 300 are pathogenic to
man
2

Also

known as mycoses

Broken

down into yeasts and molds

Yeasts

Single-cell fungi
Reproduce by budding
Very useful organisms
- Baking
- Alcoholic beverages
3

Molds
Multicellular
Characterized by long, branching
filaments called hyphae

Diseases caused Fungus

Hypersensitivity
Allergy

Mycotoxicosis
Production of toxin

Mycetismus
Pre-formed toxin

Infection

Fungal Infections

Candida

Vaginal Candidiasis

Oral thrush

Athlete's foot

Tinea

Allergic bronchopulmonary
aspergillosis
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Fungal infections
Classification
Superficial mycoses
Affect the skin, hair and nails

Subcutaneous mycoses
Affect the muscle and connective tissue
immediately below the skin

Systemic (invasive) mycoses

Involve the internal organs

Allergic mycoses
Affect lungs or sinuses
(Patients may have chronic asthma,
sinusitis)
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Opportunistic & pathogenic

fungi
Opportunistic fungi

Pathogenic fungi

Can able to produce

infection in
immunocompromised
patients

Can able to produce

infection in normal
people also

Candidiasis

Zygomycota

Aspergillosis
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Factors Causing Fungal

Infections
Damaged skin
Moist skin
Drugs (Broad-spectrum antibiotics,
immunosuppressants)

Immunocompromise
AIDS
Chronic disease

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Antifungal agents Classification

Polyene antifungal agents

- Nystain
- Amphotericin B

Azoles
- Imidazole: Ketoconazole, miconazole,
terconazole, clotrimazole, econazole
- Triazole: Fluconazole, itraconazole,
voriconazole

Allylamine

- Terbinafine

Others
- Griseofulvine & Flucytosine
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azole drugs and

terbinafine disrupt
ergosterol synthesis

griseofulvin disrupts
the mitotic spindle
nucleus

amphotericin and
nystatin form pores
in the cell membrane

flucytosine blocks
DNA synthesis
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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

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Fungal Resistance mechanism

Fungi acquire resistance by decreasing
the ergosterol content in plasma
membrane* * * *

Pharmacokinetics

Amphotericin is administered by slow,

intravenous infusion
Intrathecal route is chosen for the treatment of
meningitis caused by fungi
Amphotericin B is extensively protein bound to
plasma proteins and distributed throughout the
body
It does cross the placenta
Renal and biliary route of elimination
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Adverse Effects

- Convulsions
- Thrombophlebiti
s
- Serious
neurological
problems

peated administration of the drug will subside the probl

remedication with corticosteroid or an antipyretic helps
prevent the fever and chills.
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Adverse Effects

Dose adjustment is not required in patients

with compromised renal or hepatic function
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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

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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

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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

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Therapeutic uses
The drug of choice for
Cryptococcal meningitis
Mucormycosis (zygomycosis)
Invasive fungal infection, not responding
to other therapy

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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.

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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.
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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

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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
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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 administered together with

cola drinks
Ketoconazole is dissolved and absorbed in
acidic pH. Cola drinks enhance the absorption
of ketoconazole
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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 administered together with

Rifampin
Rifampin induce CYP 450 system and increase
the metabolism of ketoconazole. Ketoconazole
therapeutic activity is decreased
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Ketoconazole-Contraindications
Ketoconazole is contraindicated
in pregnancy
Ketoconazole should not be
administered together with
Amphotericin B

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Ketoconazole-Therapeutic uses
Fungal pneumonia
Cryptococcal meningitis
Sepsis syndrome due to fungal
infection
Mycotic corneal ulcers
Keratitis
Fungal arthritis

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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
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 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
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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

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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

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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

Griseofulvin and alcohol

Griseofulvin potentiates the intoxicating
effects of alcohol
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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
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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

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Mechanism of fungal resistance

Decreased levels of enzymes
Decreased
synthesis
of
cytosine
deaminase
decreased synthesis of thymidylate
synthase

ADR

Neutropenia, thrompbocytopenia
Bone marrow depression occasionally
Hepatotoxicity
Nausea, vomiting and diarrhea
Severe enterocolitis

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