Antifungal Drugs

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• Antifungal (Antimycotic) drugs are agents
which are used to prevent growth and
multiplication of fungi.
• Unlike bacteria, the pathogenic fungi those
affect animals are eukaryotes possessing
nuclei, mitochondria and cell membranes
containing sterols.
• The similarities between fungal and
mammalian cells therefore, work against the
selective toxicity and the fungal infections are
generally resistant to antibiotics used in the
treatment of bacterial diseases.
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• In general, fungal infections are more
difficult to treat, are slowly eradicated, and
the antifungal drugs are more toxic to host
than antibacterial drugs.

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 Fungi
• Fungi are a large group of eukaryotic
organisms which include microorganisms
such as yeasts and moulds, as well as the
mushrooms.

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• The fungal cell is surrounded by a rigid cell
wall containing chitin and polysaccharides
and a cell membrane containing a lipid
bilayer composed mainly of ergosterol.
• The cell wall provides structural support to
the fungal cell.
• Fungi generally reproduce asexually via
budding, sporulation or hyphal
fragmentation.

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• The pathogenic fungi, which cause
diseases in humans and animals generally
consist of two main groups of organisms-
moulds and yeasts.
• The moulds exist in multicellular
filamentous forms (hyphal form) whereas
yeasts have unicellular oval are spherical
appearance. Many other fungi produce
biologically active compounds, several of
which are toxic to animals or plants.
• Fig. 66.1 page 1011
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 Types of fungal infection
• Fungal infections, usually called mycoses,
have been divided into two distinct
classes:
• 1..superficial and 2.. systemic.

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 1.Superficial fungal infection
• The superficial fungal infections generally affect
the keratinised layers of skin and its appendages
(hair, feathers, horns and nails ) or mucous
membranes (buccal, gastrointestinal ,ruminal or
vaginal).
• The superficial fungal infections are generally
irritating with manifestations of alopecia,
erythema, scale formation, exudation, etc. The
lesions are frequently ring shaped hence the
disease is commonly called ringworm. 10
 2.Systemic fungal infections
• The systemic fungal infections (systemic
mycoses) affect deeper tissues and organs.
• Depending on the types of causative agent,
the fungal diseases have been named as
histoplasmosis, coccidioidomycosis,
blastomycosis, paracoccidioiodomycosis,
candidiasis, cryptococcosis, aspergillosis, etc.
• Some fungi affect dermis and subcutaneous
tissues and are generally called subcutaneous
mycoses.
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• The systemic fungal diseases are often
serious and life- threatening and are
generally difficult to treat.
• Immuno–suppression, prolonged use of
broad-spectrum antibacterial or cytotoxic
drugs, moist environment and necrotic
tissue predispose the patient to fungal
infection.

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 Anti-fungal drugs:
• Depending on the requirement , initially
two important antibiotics-amphotericin B
and griseofulvin were introduced around
1960 for systemic mycoses and
dermatophytosis, respectively.
• This was followed by flucytosine and
imidazoles in 1970s and triazoles in 1980s
• Some newer compounds such as
terbinafine have been introduced recently.
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 Selection and use of antifungal
drugs:
• The therapeutic use of antifungal agents
should be initiated only after clear
identification of the organisms because
some infections are of mixed type where a
suitable antibacterial agent must
accompany antifungal agent.

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 Classification:
• I. Antifungal antibiotics
• 1. Polyenes: amphotericin B,
nystatin(PAN)
• 2. Heterocyclic benzofurans:
griseofulvin(HG)
• II. Antimetabolites: flucytosine(AF)

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• III. Azoles:
• 1. Imidazoles: ketoconazole,
miconazole(kmI)
• 2. Triazoles: fluconazole ,
itraconazole(TFI)
• IV. Alkylamines: terbinafine, butenafine
(ATB)

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• V. Echinocandins : caspofungin,
micafungin
• VI. Iodides: sodium iodides, potassium
iodide
• VII. Miscellaneous agents:
• 1. Organic acids: benzoic acid, salicylic
acid

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• 2. Fatty acids and salts: propionates and
undecylenate
• 3. Dyes: gentian(CRYSTAL) violate
• 4. Phenols and phenolic ether: phenol,
thymol
• 5. Hydroxyquinolines: clioquinol

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• 6. Thiocarbamate: tolnaftate
• 7. Sulphur and Sulphur preparations:
sulfur and sulfiram
• 8. Copper preparations: copper sulfate
• 9. Other antifungal agents: selenium
sulphide, dichlorophen, sodium
thiosulphate, nitrofuroxine

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 AMPHOTERICIN B:
• Amphotericin (AMB) is an amphoteric
polyene antibiotic obtained from
Streptomyces nodusus.
• Two amphotericins, Amphotericin A and
Amphotericin B are known, but only B is
used clinically because it is significantly more
active in-vivo.
• Amphotericin A is almost identical to
Amphotericin B, but has little antifungal
activity. Amphotericin B is often used
intravenously for systemic fungal infections. 20
 Mechanism of action:
• The amphotericin B and other polyene
antibiotics have high affinity for sterols,
particularly ergosterol, present in fungal
cell membranes.
• The interaction of AMB and other polyene
antibiotics with membrane ergosterol
results in formation of channels or pores in
the cell membrane with altered membrane
permeability and leakage of cellular
contents. 21
• The altered K+/H+ exchange results in the
efflux of potassium and influx of hydrogen
ions, producing a state of acidosis that
halts some important enzymatic
processes.
• Loss of important organic molecules such
as amino acids and sugars from the fungal
cells results in irreversible damage.

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• High concentration of amphotericin B
directly disrupts the fungal cell membrane
permeability.
• Amphotericin B, like some other
antifungal agents, also has some
immunomodulatory action by potentiating
both humoral and cell-mediated immunity.
This enhances the host’s ability to fight
fungal infection.

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• Amphotericin B is a fungistatic at normal
dosages, but it can become fungicidal at
higher concentrations.

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 Antimicrobial spectrum:
• Amphotericin B and other polyene antibiotics
have broad –spectrum antifungal activity,
although the sensitivity of various species and
strains of fungi to these antibiotics vary widely.
• Amphotericin B is useful against several
systemic fungi including Candida,
Histoplasma, Cryptococcus, Blastomyces,
Coccidiodies, Aspergillus and Sporithrix spp.
• It has a grater activity against Candida and
Aspergillus spp. and Coccidiodal meningitis
than newer azoles. 25
• Fungal resistance:
• Ressistance to Amphotericin B is infrequent
and is rarely noted during therapy.
• Side effects/Adverse effects:
• Amphotericin B is a toxic drug with side
effects/adverse effects especially renal
function impairment, occurring in many
patients.
• The nephrotoxicity generally occurs via two
mechanisms- intense renal vasoconstriction
and binding of drug to membrane cholesterol
in the renal tubular cell membrane. 26
 NYSTATIN
• Nystatin is a polyene antifungal antibiotic
produced by Streptomyces noursei.
• It is structurally similar to Ampohotericin B
and has the same mechanism of action.
• Nystatin has activity against a variety of
fungi, but its use is restricted to fungal
infections of the skin and GI tract mainly
caused by Candida spp. (not dermatophytes)
because of its high systemic toxicity.
• It is not absorbed from skin or GI tracts, so its
topical application or GI administration is safe.
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• Nystatin is primarily used for skin, mouth,
intestinal or vaginal candidiasis in dogs,
cats and birds.
• The lesion of thrush (oral candidiasis) and
vaginitis usually respond well to nystatin.
• Combination of nystatin with antibacterial
agents and corticosteroids are also
available to enhance efficacy and to
reduce Candida superinfection.

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 Griseofulvin:
• Griseofulvin is a systemic antifungal
antibiotic obtained from Pencillium
griseofulvin.
• Although it was isolated in 1939, its
antifungal activity was demonstrated only
around 1960.

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 Mechanism of action:
• Griseofulvin is a fungistatic drug that
enters into the susceptible fungi through
energy-dependent transport system.
• It then acts by interfering with the
polymerization of the microtubular protein
with microtubules.
• Interaction with the microtubules interferes
with the spindle formation in dividing cells
thereby arresting the metaphase of cell
division. 30
• Impairment of microtubule function may
also interfere with the transport of
essential material through cytoplasm to
periphery, which accounts for inhibition of
hyphal cell wall synthesis.
• Griseofulvin also probably binds to RNA
and inhibits nucleic acid synthesis.
• It also binds to keratin precursor cells and
makes them resistant to fungal infections.

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 Antimicrobial spectrum:
• Griseofulvin is a narrow-spectrum antifungal
agent active only against dermatophytes i.e.:
Microsporum, Trichophyton and
Epidermophyton.
• Griseofulvin is unique among antifungal
antibiotics which on oral administration
accumulates into keratin (proteins) and
produces action against superficial fungi.

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• It is ineffective against deep mycoses,
Candida species and bacteria.
• Griseofulvin is a fungistatic against older
and dormant fungi, but may kill (fungicidal)
growing young cell.

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 Clinical uses

• Griseofulvin is primarily recommended

for treatment of dermatophytic fungal
infections of skin, hair and claws in dogs,
cats, calves, horses and some other
species.
• It is available for oral use as either a
microsize or ultramicrosize tablet.

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 Antimetabolites
• Flucytosine
• Flucytosine is a fluorinated pyrimidine
antifungal agent.
• It was originally synthesized as an
antineoplastic drug, but latter on it was
found to have good antifungal activity.

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 Mechanism of action:
• Flucytosine, an analogue of cytosine, is
inactive as such and requires conversion into
active metabolite inside the fungal cells.
• On administration, flucytosine enters fungal
cell via a cytosine specific permease, an
enzyme not found in mammalian cells.
• Inside the fungal cell, it is rapidly converted
into 5-flurouracil by cytosine deaminase
enzyme.
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• The 5-flurouracil act as an anti-metabolite by
competing with uracil.
• It initially forms 5-flurouracil monophosphate
and then 5-flurouracil triphosphate, which
interferes with pyrimidine metabolism and
eventually RNA and protein synthesis.

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• The 5-flurouracil monophosphate by an
alternate pathway is also metabolized to 5-
Flurourodeoxyuracil monophosphate, an
inhibitor of thymidylate synthetase.
• Inhibition of thymidylate synthetase
deprives the organisms of thymidylic acid,
an essential DNA component, which
eventually disrupts DNA synthesis and cell
division.
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• The combination of flucytosine and
amphotericin B is synergistic because
amphotericin affects fungal cell
permeability, allowing more of flucytosine
to penetrate the cell

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 Imidazoles
• Imidazoles are a group of organic
compounds in which the aromatic
heterocyclic is a diazole.
• The imidazoles include a large number of
predominantly synthetic drugs.
• They are active against many
microoraganisms and parasites including
fungi, bacteria, helminths and protozoa.

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 Mechanism of action:
• The imidazoles and triazoles act on the
fungal cell membrane and alter the
membrane permeability of susceptible
fungi by inhibition of ergosterol synthesis.
• They inhibit 14 alpha- demethylase, a
fungal microsomal cytochrome 450
dependent enzyme.
• This enzyme normally participates in the
sterol biosynthesis pathway and catalyses
demethylation lanosterol to ergosterol, the
major cell membrane component. 41
• The reduced synthesis of ergosterol content in
the cell membrane in response to azole
antifungals in turn decreases the fluidity of
membrane and increases the permeability with
effects similar to amphotericin B.
• Inhibition of ergosterol synthesis also results in
accumulation of 14 alpha-methyl sterol, which
impairs membrane functions leading to
alterations in energy metabolism and growth
inhibition. High concentrations of azole
derivatives also inhibit fatty acid and glyceride
synthesis. 42
 Ketoconazole:
• Ketoconazole is synthetic imidazole
antifungal drug for systemic use.
• It was the first azole that could be given
orally to treat systemic fungal infection and
is still considered the prototype drug.

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 Antimicrobial spectrum:
• Ketoconazole has a broad spectrum of
antifungal activity which include Candida,
Cryptococcus, Coccidioides, Blastomyces
and Hisptoplama spp.
• It is also effective against Candida and
dermatophytes like Microsporum and
Trichophyton.
• High concentrations of ketoconazole are
required to treat most strains of
Aspergillus and Sporothrix. 44
• It also possess in vitro activity against
some bacteria (e.g. Staph. aureus,
Nocardia and enterococci) and viruses
(Herpes simplex virus 1 and 2), but clinical
implications of this have not been
determined.
• It has no anti parasitic activity, with
possible exception of antiprotozoal effects
against Leishmania major.
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 Clinical uses:
• Ketoconazole has been used to treat
systemic mycoses in dogs, cats, horses,
birds and some other species.
• It is also used to treat superficial infections
those have not responded to griseofulvin
or topical antifungal therapy.

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 Fluconazole:

• Fluconazole is a synthetic triazole

antifungal drug commonly used in the
treatment and prevention of superficial and
systemic fungal infections.

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 Mechanism of action:

• Similar to imidazoles, fluconazole

inhibits the fungal cytochrome P450
enzyme 14 alpha- demethylase that
converts lanosterol to ergosterol, an
essential component of the fungal
cytoplasmic membrane.
• Mammalian demethylases activity is much
less sensitive to fluconazole than fungal
demethylase.
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 Antimicrobial spectrum:
• Fluconazole has fungistatic action
against a wide range of pathogenic fungi.
• It is effective against local and systemic
Candida spp. and systemic Cryptococcus,
Hisptoplasma, Sporothrix and Blastomyces
spp.
• It is also effective against dermatophytes.
• In general, it appears to have a wider range
of antifungal activity than ketoconazole.

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 Clinical uses:
• Fluconazole is a drug indicated for the
treatment and prophylaxis of fungal
infection where other antifungals have
failed or are not tolerated.
• It is used against dermatophytes, yeast
and a variety of systemic fungi.
• These include treatment of systemic
mycoses including cryptococal meningitis
and treatment of superficial candidiasis
and dermatophytes.
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• It is also used for the prophylaxis of
candidiasis in immunocompromised
individuals.
• It is mostly used by oral administration.
• Intravenous route may be used for severe
infections.

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 Sodium iodide
• Sodium iodide is occasionally used in the
treatment of fungal infections.
• The mechanism of antifungal infection of
iodides is not well understood.
• After oral administration, sodium iodide is
rapidly and completely absorbed from the
GI tract and freely distributed into
extracellular fluid and glandular secretions.
• It accumulates in the thyroid gland and to
lesser extent in salivary, lachrymal and
tracheobronchial glands. 52
 Potassium iodide

• Potassium iodide possesses antifungal

actions similar to those of sodium iodide.
However, it is less commonly used than
the sodium iodide.
• Similar to sodium iodide, it is used as a
20% solution for oral or IV administration.

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 Benzoic acid:
• Benzoic acid has both bacteriostatic and
fungistatic actions.
• For funagal infections, it is mostly combined
with salicyclic acid to make Whitfield ointment.
It is considered useful against superficial
dermatophyte infections, particularly
Trichophyton infection, in cattle and man.
• Benzoic acid and its salts are used as a food
preservative and inhibit the growth of mould,
yeast and some bacteria.
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 Propionic acid:
• Propionic acid is a naturally occurring
carboxylic acid. It inhibits the growth of
mould and some bacteria at levels
between 0.1-1% weight.
• Propionate salts (sodium and calcium
propionate) are used as mould inhibitors
and preservatives for both animal feed and
food for human consumption and as a
topical antifungal agent.
• Sodium propionate is useful in the
treatment of dermatophytosis in
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concentration of 1%-5%.
 Gentian violet

• Gentian violet (crystal violet) is a dye.

• The dye is used as a histological stain and
in Gram’s Method of classifying bacteria.
• It has antibacterial, antifungal and
anthelminthic properties and is
occasionally used as a topical antiseptic.

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 Sulphur

• Sulphur is a multi-valent non–metal

with multiple uses including as a drug.
• Sulphur is externally used as an ointment,
powder or lotion for various skin diseases
such as ringworm and eczema(.
Inflammation of skin)
• It is also used externally as parasiticide,
insecticide and disinfectant.

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 Copper sulphate:
• Copper sulphate, also known as cupric
sulphate, is the chemical compound.
• Copper sulphate applied topically is considered
useful against ringworm infection.
• The fungicidal action is produced partly by the
virtue of its astringent and caustic nature and
partly by the antifungal action of copper ion.
• It is used as ointment or paste in strengths of
up to 5% or as aqueous solutions of 1-2%.

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