Medicinal Chemistry and Pharmacology of Antifungal Agents and how to take care from fungal infections. Useful Course study material for the undergraduate , postgraduate and aspirants of Pharmacy , Pharmacology and Medicinal Chemistry.

1. ANTIFUNGAL DRUGS
Dr. Amit G. Nerkar,
M.Pharm, PhD., CCP., FAFSER
Founder and Director,
Ateos Foundation of Science Education and
Research, Pune, M.S., India

2. Fungiis:
Eukaryotic – a true nucleus
Do not contain chlorophyll
Have cell walls
Produce filamentous structures
Produce spores
Contain ergosterol
The Term mycosis (plural: mycoses) refers
to conditions in which fungi pass the
resistance barriers of the human or animal
body and establish infections.

9. • A yeast infection results from an overgrowth of yeast (a type of fungus) anywhere in the
body. Candidasis is by far the most common type of yeast infection. There are more than 20
species of Candida, the most common being Candida albicans. These fungi live on all surfaces
of our bodies. Under certain conditions, they can become so numerous they cause infections,
particularly in warm and moist areas. Examples of such infections are vaginal yeast
infections, thrush (infection of tissues of the oral cavity), skin, including diaper rash, beneath
large breasts, and nailbed infections.
• Candida infections commonly occur in warm moist body areas, such as underarms. Usually
your skin effectively blocks yeast, but any breakdown or cuts in the skin may allow this
organism to penetrate.
• Typical affected areas in babies include the mouth and diaper areas.
• Vaginal yeast infection, which is the most common form of Vaginitis is often referred to as
vaginal Candidiasis.
• In adults, oral yeast infections become more common with increased age. Adults also can
have yeast infections around dentures, in skin folds under the breast and lower abdomen,
nailbeds, and beneath other skin folds. Most of these candida infections are superficial and
clear up easily with treatment. Infections of the nailbeds often require prolonged therapy.
• Rarely, the yeast infection may spread throughout the body. In systemic candidal disease (in
which the fungus enters the bloodstream and spreads throughout the body), up to 45% of
people may die. Even common mouth and vaginal yeast infections can cause critical illness
and can be more resistant to normal treatment.
• Yeast infections that return may be a sign of more serious diseases such
as diabetes, leukemia, or AIDS.

14. damp.

18. Targets for Antifungal agents
- Generally these targets should be different from mammalians.
- Both human and fungi are eukaryotic, so not much difference could be found.
- The most important difference is the presence of cell wall for fungi that is not
found in humans.
- Other targets are:
- Inhibitors of DNA synthesis.
- Disruption of mitotic spindle.
- Interfere with metabolism.
- The most exploited difference is the nature of sterols:
- Important components of cell membrane for proper function of cell membrane
enzymes and ion transporter proteins.

19. Targets for Antifungal agents

21. , Terbinafine

23. Mechanism of action of antifungal Agents

24. Targets for Antifungal agents
- Mammalians contain cholesterol while fungi posses ergosterol.
- The difference is in the side chain of ergosterol which is more flat compared
to cholesterol;
- A difference that is responsible for providing selectivity for the majority of
antifungal agents.
Cholesterol Ergosterol

25. Polyene membrane disrupters
- Polyenes: macrocyclic lactones with distinct hydrophilic and lipophilic
regions.
- Produced from Streptomyces species
- Hydrophilic: alcohol, carboxylic acids, sugar.
- Lipophilic: contain a pharmacophore of 4-7 conjugated double bonds.
- The number of the double bonds correlate directly to activity and inversely to
toxicity.
- Amphotericin is 10X more active which can be taken systemically.
- Mechanism of action: have affinity to ergosterols containing membranes, then
inserted in the cell membrane, disrupts its function, leak of cell components.

26. Amphotericin

27. Polyene membrane disrupters
1- Nystatin:
- A tetraene agent that used topically.
- No oral absorption, so used orally for mouth and GIT infections.
2- Amphotericin B:
- Heptaene derivative with low enough toxicity for I.V use, but still toxic drug
used with caution.
- It does not cross BBB, so used intrathecally of brain fungal infections.
- The main side effect is nephrotoxicity, reduced by formulation change.
- Liposomal encapsulation was found to target infected tissues as the capillary
size at the infected areas is larger, so release the drug specifically at that area.

28. Nystatin
Amphotericin nephrotoxicity

29. Ergosterol Biosynthesis inhibitors
A- Azoles:
- The largest group of antifungal agents.
- Some used topically and others used systemically.
- some are orally bioavailable with broad spectrum properties.
- SAR:
- 5-membered ring with 2-3 Ns.
- side chain attached to N.
- At least has one aromatic ring.
- Mechanism of action:
- Act by inhibiting ergosterol synthesis by inhibiting CYP450 14-α-
demethylase, where the basic nitrogen N3 of the drug bind to heme iron
of the enzyme blocking the active site.

30. R R
CO2H
CO2 R
Fe-Cyt P-450
Lanosterol Carboxylate Ergosterol
N
N
N
N Fe-Cyt P-450
Fe-Cyt P-450
Mechanism of action of Azoles

31. Ergosterol Biosynthesis inhibitors
- Inhibition will lead to accumulation of sterols with extra methyl group.
- This new sterol structure does not have the shape and physical
properties of the normal ones, leading to permeability changes.
- Selectivity to mammalian C450 compared to the fungal one is 1:1000,
and even, most of azoles considered mammalian C450 inhibitors which
lead to serious drug-drug interactions in some cases.
- Systemic azoles are : Ketoconazole, Itraconazole, Fluconazole and
voricanazole.
- Non-systemic azoles are : Clotrimazole, Oxiconazole and miconazole.

32. Ergosterol Biosynthesis inhibitors
1. Ketoconazole:
- Imidazole derivative, that is
orally active for systemic infections.
- Depends mainly on low stomach pH for absorption.
- Inhibit C450 causing serious drug-drug interactions.
- All its metabolites are inactive and mainly used topically.

33. Ergosterol Biosynthesis inhibitors
Ketoconazole Metabolism:
- Deacylation.
- Aromatic hydroxylation.
Hydroxylation
Binds heme active site
Deacylation

34. Ergosterol Biosynthesis inhibitors
2- Itraconazole:
- Triazole derivative.
- Oral bioavailability depend on food and stomach pH.
- highly interfere with liver enzymes (serious drug drug interactions).
3- Fluconazole:
- Equal bioavailability, oral and I.V.
- Could cross BBB (Why?).
- Weak inhibitor to some liver enzymes.

35. Ergosterol Biosynthesis inhibitors
B- Allylamines:
- They have limited spectrum of activity which is only used for
dermatophytes.
- Includes: Naftifine, Terbinafine, and Tolnaftate
- Mechanism of action: inhibit squalene epoxidase,
- leading to build up of squalene that it self is toxic compound.
- and also lead to reduction of sterol levels in cell membrane,
leading to cell lysis.
- Mammalian squalene epoxidase is less sensitive to these drugs.

36. O
HO HO
Ergosterol
Squalene
Epoxidase
Steps
Lanosterol
Steps

37. Ergosterol Biosynthesis inhibitors
-Terbinafine:
- Topical and Oral.
- Active against many dermatophytes.
- Highly lipophilic.
- Extensively metabolized.

38. Ergosterol Biosynthesis inhibitors
C- Morpholines:
- Amorolfine:
- The only drug of this class, used topically.
- Act on Δ14 reductase enzyme, and Δ8, Δ7 isomerase enzymes.
- produce non-similar compounds with different physical
properties, leading to cell leakage.

39. Miscellaneous mechanism of actions
- Flucytosine:
- Powerful agent for systemic infections.
- Taken up by fungal cells and interferes with
DNA synthesis
- Prodrug to produce 5-flurouracil.
- Griseofulvin:
- Orally taken for superficial infections.
- Not used topically.
- Bind to protein tubulin.
- Interfere with cell division.

40. N
N
H
NH2
F
O
HN
N
H
O
F
O
HN
N
O
F
O
O
P
O
O
O
O
OH
Cytosine
Deaminase
5-Flurouracil
5-Flurodeoxyuridine
monophosphate

42. Chemical Classification……………..

43. Chemical Classification…..contd…

44. Mixed Classification:

47. • ANTIFUNGAL ANTIBIOTICS:
• Amphotericin B
• Nystatin
• Griseofulvin

48. Polyene antifungal:
hydrophobic
hydrophilic
Polyene antifungals:-
A polyene is a circular molecule consisting of a
hydrophobic and hydrophilic region.
The polyene antimycotics bind with sterols in the
fungal cell membrane, principally ergosterol. As a
result, the cell's contents leak out (usually the
hydrophilic contents) and the cell dies. Animal cells
contain cholesterol instead of ergosterol and so
they are much less susceptible. (Note: as
polyene's hydrophobic chain is reduced, its sterol
binding activity is increased. Therefore, increased
reduction of the hydrophobic chain may result in it
binding to cholesterol, making it toxic to animals.)

49. Chemistry :
Polyene antifungal:
hydrophobic
hydrophilic

54. Structure activity relationship (SAR):
Polyene antifungal Antibiotics:
hydrophobic
hydrophilic

55. Polyene antifungal:
Structure activity relationship (SAR):
The polyene antibiotic produced by
actinomycetes contain alarge lactone ring
with 4 to 7 unsubstituted conjugated double
bond .
The conjugated system are usually in all-
trans configuration so that the ring contains
a planner lipophilic segment and a less rigid
hydrophilic portion.
With increase conjugation (double bond)
the activity and toxicity will increase.
The polyenes have polyhydroxyl groups.

56. Structure activity relationship (SAR):
Amphotericin B have 7conjugated double bond
while nystatin have 6 conjugated double bond so,
amphotericin B more active and more toxic.
Most polyene antifungal drugs are macrocyclic
lactones.
Ring sizes varying from 12 to 37 atoms in size .
Polyene antifungal:

57. Amphtericin B
Nystatin

58. polyene antifungal drug.
Used intravenously for systemic fungal
infections.
It was originally extracted from
Streptomyces nodosus, a filamentous
bacterium.
There areTwo amphotericins:
Amphotericin A and Amphotericin B
only B is used clinically.
Amphtericin B

59. Amphtericin B
Uses and spectrum:
Amphotericin B for injection (IV) administered
primarily to patients with progressive, potentially life-
threatening fungal infections such as:
 Aspergillosis
 cryptococcosis (torulosis)
 North American blastomycosis
 systemic candidiasis
 coccidioido-mycosis
 histoplasmosis
 zygomycosis including mucormycosis
Its spectrum is the broadest of all antifungals.

60. Amphotericin B : Antifungal Spectrum

61. Amphtericin B
Precaution:
Acute reactions including fever, shaking chills,
hypotension, anorexia, nausea, vomiting, headache,
and tachypnea are common 1 to 3 hours after starting
an intravenous infusion.
Rapid intravenous infusion.
Whenever medication is interrupted for a period
longer than 7 days, therapy should be resumed by
starting with the lowest dosage level.
Pregnancy: Teratogenic Effects, category B.
Nursing Mothers
Pediatric Use

62. Amphtericin B
Contraindication:
This product is contraindicated in those patients
who have shown hypersensitivity to
Amphotericin B or any other component in the
formulation.

63. Amphtericin B
Pharmacokinetic:
Poorly absorbed from GIT.
Start with small initial dose then gradually increase it.
An elimination half-life approximately 15 days.
Amphotericin B circulating in plasma is highly bound
(>90%) to plasma proteins.
Amphotericin B is excreted very slowly (over weeks
to months) by the kidneys.
After treatment is discontinued, the drug can be
detected in the urine for at least seven weeks.

64. Amphtericin B
Side effects:
acute reaction:
 fever
 shaking chills
 hypotension
 anorexia
 nausea
 vomiting
 headache
 dyspnea
 tachypnea

65. Side effects
Nephrotoxicity (kidney damage).
Electrolyte imbalances (e.g. hypokalemia and
hypocalcemia).
Increased liver enzymes and hepatotoxicity up to
acute liver failure.
several forms of anemia.
serious cardiac arrhythmias.
Skin reactions.
Amphtericin B

66. Amphtericin B
Drug interaction:
Flucytosine
Diuretics or Cisplatin
Corticosterioids
Cytostatic drugs
Foscarnet, Ganciclovir, Tenofovir, Adefovir

67. Drug interaction:
Nephrotoxic medications: agents such as
aminoglycosides, cyclosporine, and
pentamidine.
Imidazoles (e.g., ketoconazole,
miconazole, clotrimazole, fluconazole, etc.)
Skeletal muscle relaxants.
Digitalis glycosides.
Amphtericin B

68. Nystatin
Drug description:
Nystatin is an antimycotic polyene antibiotic
obtained from Streptomyces noursei.
Nystatin is a polyene antifungal drug to which many
molds and yeast infections are sensitive, including
Candida spp.
Nystatin has some toxicity associated with it when
given intravenously, but it is not absorbed across
intact skin or mucous membranes.

69. It is considered a relatively safe drug for treating oral
or gastrointestinal fungal infections.
It is only insoluble in water and sparingly soluble in
organic solvent. It is unstable to moisture, heat and
light.
Administered orally in the treatment of gastrointestinal
candidiasis and oral thrush, intestinal monilial
infection.
Drug of choice for vaginal & cutaneous candidiasis.
Administered in vaginal tablets or topically, sometimes
combined with iodochlorohydroxyquine.

70. This product is available in the following dosage
forms:
Suspension
Tablet
Capsule
Spectrum and Uses:
Nystatine has awide spectrum of antifungal activity,
nystatine used for Cutaneous, vaginal, mucosal and
esophageal Candida infections.
Cryptococcus is also sensitive to nystatin.
treating neonatal oral thrush.

71. Brand names:
Nystan Infestat
Nystalocal
Nystamont
Nystop
PRECAUTION:
General
This medication is not to be used for the treatment of
systemic mycoses. Discontinue treatment if
sensitization or irritation is reported during use.
Carcinogenesis, Mutagenesis, Impairment of
Fertility:
There also have been no studies to determine
mutagenicity or whether this medication affects
fertility in males or females.

72. Pregnancy:
Teratogenic Effects:
Category C. Animal reproduction studies have not
been conducted with nystatin oral suspension. Nystatin
oral suspension should be given to a pregnant woman
only if clearly needed.
Nursing Mothers:
It is not known whether nystatin is excreted in human
milk. Because many drugs are excreted in human milk,
caution should be exercised when nystatin is
administered to a nursing woman.

73. SIDE EFFECTS:
Nystatin is well tolerated even with prolonged therapy.
Oral irritation and sensitization have been reported.
Gastrointestinal: Diarrhea ,nausea, vomiting,
gastrointestinal upset/disturbances.
Dermatologic: Rash, including urticaria has been
reported rarely.
Other: Tachycardia, bronchospasm, facial swelling.

74. Pharmacokinetics:
Gastrointestinal absorption of nystatin is insignificant
(poorly absorbed).
Most orally administered nystatin is passed unchanged
in the stool.
In patients with renal insufficiency significant plasma
concentrations of nystatin may occur.
Microbiology:
Nystatin is both fungistatic and fungicidal gainst a
wide variety of yeasts and yeast-like fungi.
Candida albicans demonstrates no significant
resistance to nystatin on repeated subculture in
increasing levels of nystatin other Candida species
become quite resistant.

75. OVERDOSE:
Oral doses of nystatin in excess of five million units
daily have caused nausea and gastrointestinal upset.
CONTRAINDICATION:
The preparation is contraindicated in patients with a
history of hypersensitivity to any of its components.

76. Non polyenes antifungals
Griseofulvin: The drug binds to tubulin, interfering
with microtubule function, thus inhibiting mitosis.
It binds to keratin in keratin precursor cells and
makes them resistant to fungal infections. It is only
when hair or skin is replaced by the keratin-
griseofulvin complex that the drug reaches its site
of action. Griseofulvin will then enter the
dermatophyte through energy dependent transport
processes and bind to fungal microtubules. This
alters the processing for mitosis and also
underlying information for deposition of fungal cell
walls.

77. Brand Names:
Fulvicin P/G, Fulvicin U/F, Grifulvin V, Gris-PEG,
Grisactin 250, Grisactin 500, Grisactin Ultra
Penicillium niciklium griseofulvum.
Spectrum of activity and Resistance:
1) Effective against various species of Trichophyton,
Microsporum, and Epidermophyton
2) Not effective against candida and bacteria
Griseofulvin

78. Structure Activity Relationship:
Four possible stereoisomers only (+)-enantiomer
is active
Cl replaced by F → same activity
Cl replaced by Br or H → ↓ activity
Placement of the halogen on C5 → ↓ activity
Replacement of CH3O on ring C with either
propoxy or butoxy functions → ↑ activity

79. Mechanism of action :
Binds to keratin
disrupts the cell's mitotic spindle structure
cause defective DNA synthesis
interferes with tubulin polymerization
Resistance:
is due to alteration of the drug's target site,
by mutation of ribosome sequences.
Griseofulvin

80. Uses:
is effective against dermatophytes but yeast-like
fugi are less susceptible.
Tinea capitis (ringworm of the scalp)
Tinea cruris (ringworm of the high)
Tinea corporis (ringworm of the body(
Tinea unguium (onychomycosis)
Tinea barbae (barber's itch)
Tinea :
species of fungus that causes ringworm
Griseofulvin

81. Griseofulvin
Side effects:
Skin rashes
Dizziness
Fatigue
Headache
Vomiting
Swelling
Loss of taste sensation
Tingling in the hands or feet
Oral thrush (yeast infection of the mouth)

82. Drug interactions:
cause
drug
stop its absorption.
Antacids and H2
antagonists
nausea and vomiting
alcohol
(thinning the blood less than required)
because Griseofulvin increase liver
enzyme reducing the concentration of
warfarin
Warfarin
(increasing the chance of pregnancy)
because Griseofulvin cause increase in
liver enzyme reducing the concentration
of Oral contraceptive
Oral contraceptive

83. Pharmacokinetic:
Oral
Diatery fat increase absorption
Half life 9-21 hours
Demethylated and conjugated with glucuronide
Precautions:
use machines or do other things that could be
dangerous if you are dizzy. Stay out of direct
sunlight..
Griseofulvin

84. Griseofulvin
Amphotericin B
Nystatin
Loss of taste sensation
Tingling ,Oral thrush
Nephrotoxicity,
hepatotoxicity, cardiac
arrhythmias & anemia
SE: Oral irritation
and sensitization
Binds to keratin>>>
disrupts mitotic spindle
structure>>>defective
DNA synthesis>>>
interferes with tubulin
polymerization
MOA: bind to ergosterol in cell memb. >>>
leakage of ions >>> cell death.
oral
IV
ROA: topical,and orally
widely
SOU: widely

85. Classificationofantifungals
Examples:
* Natamycin -- 33 Carbons, binds well to ergosterol
* Rimocidin
* Nystatin
* Amphotericin B

86. Natamycin 33 Carbons
Natamcyin is able to inhibit growth of fungi by inhibiting transport of amino
acids and glucose across the plasma membrane. Natamycin performs this function by specifically
binding to ergosterol and inhibiting membrane transport proteins.
Natamycin has a very low solubility in water; however, natamycin is effective at very low levels.
Its minimum inhibitory concentration is less than 10 ppm for most molds.
Natamycin was first isolated in 1955 from fermentation broth of a Streptomyces natalensis cell
culture. It is applied topically as a cream, in eye drops, or (for oral infections) in a lozenge. It
shows negligible absorption into the body when administered in these ways. When taken
orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for
systemic infections
Natamycin, also known as pimaricin, is an antifungal medication used to treat fungal infections
around the eye. This includes infections of the eyelids, conjunctiva, and cornea.
It is used as eye drops.[Natamycin is also used in the food industry as a preservative.

87. Hamycin is obtained from a strain of streptomyces bacteria growing in soil
i.e., Streptomyces pimprina. This compound is being produced in India by Hindustan
Antibiotics Limited, located at Pimpri, Pune, Maharashtra, India. It is similar to nystatin and
it is more water-soluble.
Hamycin
Hamycin is a polyene antimycotic organic compound described in India. It is a
heptaene antifungal compound rather similar in chemical structure to amphotericin
B except that it has an additional aromatic groupbonded to the molecule. When pure,
hamycin is a yellow, powdered solid. There are two versions of hamycin with very
similar chemical structures: Hamycin A and Hamycin B

88. • ANTIMETABOLITES:
Flucytosine

89. 5-Flucytosine
Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains
of Candida or Cryptococcus neoformans. It can also be used for the treatment
of chromomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not
be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast
development of resistance, but rather in combination with amphotericin B and/or azole antifungals such
as fluconazole or itraconazole. Minor infections such as candidal cystitis may be treated with flucytosine
alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a
therapeutic option, particular if the disease is life-threatening.Serious fungal infections may occur in those
who are immunocompromised. These people benefit from combination therapy including flucytosine, but the
incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.
N
N
H
NH2
F
O
HN
N
H
O
F
O
HN
N
O
F
O
O
P
O
O
O
O
OH
Cytosine
Deaminase
5-Flurouracil
5-Flurodeoxyuridine
monophosphate

90. MOA-Two major mechanisms of action have been elucidated:
•Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes
further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA
biosynthesis thus disturbing the building of certain essential proteins.
•Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate
which inhibits fungal DNA synthesis.
Spectrum of susceptible fungi and resistance
Flucytosine is active in vitro as well as in vivo against some strains
of Candida and Cryptococcus. Limited studies demonstrate that flucytosine may be of
value against infections with Sporothrix, Aspergillus, Cladosporium, Exophila,
and Phialophora. Resistance is quite commonly seen as well in treatment-naive
patients and under current treatment with flucytosine. In different strains
of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained
from patients.
5-Flucytosine

93. • AZOLES
Imidazoles: Ketoconazole,clotrimazole,
oxiconazole, miconazole
Triazoles: Floconazole, Itraconazole
Voriconazole , Posaconazole

94. Imidazole and triazole antifungals
The imidazole and triazole antifungal drugs inhibit
the enzyme cytochrome P450 14α-demethylase.
This enzyme converts lanosterol to ergosterol, and
is required in fungal cell membrane synthesis.
These drugs also block steroid synthesis in
humans.
* Miconazole (Miconazole nitrate)
* Clotrimazole - marketed as Lotrimin
The triazoles are newer, and are less toxic and
more effective
* Fluconazole
* Itraconazole

98. Azoles Mechanism of Action

103. • Azoles
Ketoconazole, Miconazole, clotrimazole,
Oxiconazole

104. Ketoconazole
1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy ] phenyl ]
piperazin -1-yl] ethanone

105. Ketoconazole
Uses:

106. Miconazole
Uses
Miconazole is used to treat skin infections such as athlete's foot, jock itch, ringworm,
and other fungal skin infections (candidiasis). This medication is also used to treat a
skin condition known as pityriasis (tinea versicolor), a fungal infection that causes a
lightening or darkening of the skin of the neck, chest, arms, or legs. Miconazole is an
azole antifungal that works by preventing the growth of fungus. This medication is
used to treat vaginal yeast infections. Miconazole reduces vaginal burning,itching,
and discharge that may occur with this condition.
How to use Miconazole Nitrate 2 % Topical Cream
Use this medication on the skin only. Clean and thoroughly dry the area to be treated.
Apply this medication to the affected skin, usually twice a day or as directed by your
doctor. If you are using the spray form, shake the bottle well before applying. Dosage
and length of treatment depends on the type of infection being treated. Do not apply
this more often than prescribed.
1-{2-[(2,4-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole nitrate

107. Clotrimazole
Clotrimazole is used to treat skin infections such as athlete's foot, jock itch, ringworm,
and other fungal skin infections (candidiasis). This medication is also used to treat a
skin condition known as pityriasis (tinea versicolor), a fungal infection that causes a
lightening or darkening of the skin of the neck, chest, arms, or legs. Clotrimazole is an
azole antifungal that works by preventing the growth of fungus.
How to use Clotrimazole Solution
Use this medication on the skin only. Clean and thoroughly dry the area to be treated.
Apply this medication to the affected skin, usually twice a day or as directed by your
doctor. Dosage and length of treatment depends on the type of infection being treated.
1-[(2-Chlorophényl)(diphényl)méthyl]-1H-imidazole

108. Oxiconazole
Oxiconazole (trade names Oxistat in the US, Oxizole in
Canada) is an antifungal medication typically administered
in a cream or lotion to treat skin infections, such
as athlete's foot, jock itch and ringworm. It can also be
prescribed to treat the skin rash known as tinea versicolor,
caused by systemic yeast overgrowth (Candida spp.).
(Z)-1-(2,4-dichlorophenyl)-N-[(2,4-dichlorophenyl)methoxy]-2-imidazol-1-ylethanimine;nitric acid

109. • AZOLES
Triazoles: Fluconazole, Itraconazole
Voriconazole

110. Triazoles
• First-generation Itracon-azole and fluconazole
were some of the first triazoles synthesized,
but had limitations associated with their use.
• Second-generation triazoles such as
voriconazole, posaconazole, albaconazole,
efinaconazole, ravuconazole and
isavuconazole are all derivatives of either
itraconazole or fluconazole.

112. Fluconazole
2-(2,4-difluorophenyl)-1,3-bis
(1,2,4-triazol-1-yl) propan-2-ol

113. Fluconazole
Uses:

114. Itraconazole
4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-l] methoxy]
phenyl] -1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

115. Itraconazole
Uses

116. Voriconazole
(αR,βS)-α-(2,4,-difluorophenyl)-5-fluoro-β-
methyl-α-(1H-1,2,4-triazol-1-yl-methyl)-4-
pyrimidineethanol

117. Voriconazole

118. Posaconazole
4-[p-[4-[p-[[(3R,5R)-5-(2,4-Difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl]
methoxy] phenyl]-1-piperazinyl]phenyl]-1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-Δ2-1,2,4-triazolin-5-one

119. Invasive Aspergillus & Candida Infections
Oral suspension or delayed-release tablets are indicated for prophylaxis of
invasive Aspergillus and Candida infections in patients who are at high risk of
developing these infections due to being severely immunocompromised (eg,
hematopoietic stem cell transplant recipients with GVHD, hematologic
malignancies with prolonged neutropenia from chemotherapy)
Oral suspension: 200 mg (5 mL) PO TID
Tablet: 300 mg PO BID on Day 1, then 300 mg PO qDay
IV: 300 mg IV BID on Day 1, then 300 mg IV qDay (see IV preparation and
administration)
Duration of therapy is based on recovery from neutropenia or
immunosuppression
Oropharyngeal Candidiasis
Oral suspension is indicated for oropharyngeal candidiasis
100 mg (2.5 mL) PO BID on Day 1, then 100 mg PO qDay for 13 days
Refractory to itraconazole and/or fluconazole: 400 mg (10 mL) PO BID; duration
based on severity of underlying disease and clinical response

122. ALLYAMINES:
Terbinafine, Butenafine

123. Terbinafine

125. Butenafine
Butenafine hydrochloride is a synthetic benzyl amine antifungal.
Butenafine is indicated for the topical treatment of tinea (pityriasis) versicolor due to Malassezia
furfur, as well as athlete's foot (Tinea pedis), ringworm (Tinea corporis) and jock itch (Tinea
cruris) due to Epidermophyton floccosum, Trichophyton mentagrophytes, Trichophyton rubrum,
and Trichophyton tonsurans. It also displays superior activity against Candida albicans than
terbinafine and naftifine. Butenafine demonstrates low minimum inhibitory concentrations
against Cryptococcus and Aspergillus. There is some evidence that it is effective against
dermatophyte infections of the toenails, but needs to be applied daily for prolonged periods (at
least one year).Butenafine is typically available as a 1% topical cream.
Like the allylamine antifungals, butenafine works by inhibiting the synthesis of ergosterol by
inhibiting squalene epoxidase, an enzyme responsible for the creation of sterols needed in
fungal cell membranes. Lacking ergosterol, the cell membranes increase in permeability,
allowing their contents to leak out.

126. Naftifine
Naftifine has triple action: antifungal, antibacterial and anti-inflammatory.
Its precise mechanism of action is unknown, but may involve selectively
blocking sterol biosynthesis via inhibition of the squalene 2,3-epoxidase
enzyme.The half-life is approximately 2–3 days.The metabolites are
excreted in the urine and feces.
Naftifine is an allylamine antifungal drug for the topical treatment
of tinea pedis, tinea cruris, and tinea corporis (fungal infections)
(E)-N-Methyl-N-(3-phenyl-2-propenyl)-1-naphthalenemethanamine

127. Echinocandins
Caspofungin, anidulafungin, micafungin

128. Echinocandins

129. History
• Discovery of echinocandins stemmed from studies on papulacandins isolated from a
strain of Papularia sphaerosperma (Pers.), which were liposaccharide - i.e., fatty acid
derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase -
and had action only on Candida spp. (narrow spectrum).
• Screening of natural products of fungal fermentation in the 1970s led to the discovery
of echinocandins, a new group of antifungals with broad-range activity
against Candida spp.
• One of the first echinocandins of the pneumocandin type, discovered in 1974,
echinocandin B, could not be used clinically due to risk of high degree of hemolysis.
• Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first
echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later
withdrawn for a toxicity due to the solvent system needed for systemic administration.
• The semisynthetic pneumocandin analogs of echinocandins were later found to have
the same kind of antifungal activity, but low toxicity.
• The first approved of these newer echinocandins was caspofungin, and later micafungin
and anidulafungin were also approved.
• All these preparations so far have low oral bioavailability, so must be given
intravenously only. Echinocandins have now become one of the first-line treatments
for Candida before the species are identified, and even as antifungal prophylaxis in
hematopoietic stem cell transplant patients.

130. Echinocandins
Chemistry
The present-day clinically used echinocandins are semisynthetic
pneumocandins, which are chemically lipopeptide in nature, consisting of
large cyclic (hexa)peptoid. Caspofungin, micafungin, and anidulafungin are
similar cyclic hexapeptide antibiotics linked to long modified N-linked acyle
fatty acid chains. The chains act as anchors on the fungal cell membrane to
help facilitate antifungal activity. Due to their limited oral bioavailability,
echinocandins are administered through intravenous infusion.

131. Echinocandins
• Advantages of echinocandins:
• broad range (especially against all Candida), thus can be given empirically
in febrile neutropenia and stem cell transplant
• can be used in case of azole-resistant Candida or use as a second-line
agent for refractory aspergillosis
• long half-life (polyphasic elimination: alpha phase 1–2 hours + beta phase
9–11 hours + gamma phase 40–50 hours)
• low toxicity: only histamine release (3%), fever (2.9%), nausea and
vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely
allergy and anaphylaxis
• not an inhibitor, inducer, or substrate of the cytochrome P450 system, or
P-glycoprotein, thus minimal drug interactions
• lack of interference from renal failure and hemodialysis
• no dose adjustment is necessary based on age, gender, race
• better (or no less effective) than amphotericin B and fluconazole against
yeast infections

132. Disadvantages of Echinocandins
• Disadvantages of echinocandins:
• embryotoxic in animal studies (category C)
thus should be avoided if possible in
pregnancy
• needs dose adjustment in liver disease
• poor ocular penetration in fungal
endophthalmitis

133. Caspofungin
Echinocandins noncompetitively inhibit
beta-1,3-D-glucan synthase enzyme
complex in susceptible fungi to disturb
fungal cell glucan synthesis. Beta-glucan
destruction prevents resistance against
osmotic forces, which leads to cell
lysis. They have fungistatic activity
against Aspergillus species. and fungicidal
activity against most Candida spp.,
including strains that are fluconazole-
resistant. In vitro and mouse models show
echinocandins may also enhance host
immune responses by exposing highly
antigenic beta-glucan epitopes that can
accelerating host cellular recognition and
inflammatory responses.

134. Caspofungin

135. Anidulafungin
Anidulafungin is manufactured via semisynthesis. The starting material
is echinocandin B (a lipopeptide fermentation product of Aspergillus
nidulans or the closely related species, A. rugulosus), which undergoes
deacylation (cleavage of the linoleoyl side chain) by the action of a
deacylase enzyme from the bacterium Actinoplanes utahensis in three
subsequent synthetic steps, including a chemical reacylation, the
antifungal drug anidulafungin is synthesized.
Candidemia and other forms of invasive Candida infections (intra-
abdominal abscess and peritonitis)
Esophageal candidiasis
Anidulafungin has not been studied in endocarditis, osteomyelitis,
and meningitis due to Candida, and has not been studied in sufficient numbers
of neutropenic patients to determine efficacy in this group.
Indications

136. Other topical Antifungals:
Tolnaftate, Undecylenic Acid, Benzoic Acid,
Haloprogin

137. Haloprogin
Haloprogin
Haloprogin was previously used in 1%
topical creams as an antifungal agent.
It was marketed over-the-
counter primarily to
treat tinea infections of the skin. The
mechanism of action is unknown.
Haloprogin had a high incidence of
side effects including: irritation,
burning, vesiculation (blisters), scaling,
and itching. It has since been
discontinued due to the emergence of
more modern antifungals with fewer
side effects.

138. Tolnaftate, Ciclopirox , Benzoic acid
Tolnaftate is a synthetic thiocarbamate used as
an anti-fungal agent that may be sold without
medical prescription in most jurisdictions. It is
supplied as a cream, powder, spray, and liquid
aerosol. Tolnaftate is used to treat fungal conditions
such as jock itch, athlete's foot and ringworm.

139. Ciclopirox
Ciclopirox is indicated for the treatment of tinea pedis and tinea
corporis due to Trichophyton rubrum, Trichophyton
mentagrophytes and Epidermophyton floccosum, as well as seborrheic
dermatitis. It is not to be used in the eyes or vagina, and nursing women
should consult their doctors before use, since it is not known whether
ciclopirox passes into human milk.

141. Topical Agents in Dermatophytosis

142. Topical Agents in Dermatophytosis

144. Clinical Spectrum of Antifungals

145. Important Features