6.ANTIFUNGAL DRUGS

BYBY
Dr.Dr. SAMINATHAN KAYAROHANAMSAMINATHAN KAYAROHANAM
M.PHARM, M.B.A, PhDM.PHARM, M.B.A, PhD
ANTIFUNGAL DRUGS
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6

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NUM CONTENT SLIDE
1 OVER VIEW OF ANTIFUNGAL DRUGS 4-8
2 TYPES OF FUNGAL INFECTIONS 9-25
3 COMMON FUNGAL INFECTIONS AND THEIR
SENSITIVITY TO VARIOUS CLASSES OF ANTIFUNGALS
26
4 CHEMICAL STRUCTURES OF ANTIFUNGAL DRUGS 27
5 CLASSIFICATION OF ANTIFUNGAL 28,29
6 SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS 30-32
7 ANTI FUNGAL DRUGS MECHANISAM 33
8 MECHANISM OF AMPHOTERICIN B 34
9 MECHANISM OF FLUCYTOSINE 35
10 MECHANISM OF KETOCONAZOLE 36
11 MECHANISM OF TERBINAFINE 37
12 MECHANISM OF GRISEOFULVIN 38
13 SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS 39
14 SOME ADVERSE REACTIONS OF AMPHOTERICIN B 40
15 PHARMACOLOGIC PROPERTIES OF FOUR SYSTEMIC
AZOLE DRUGS
41

3
LEARNING OUTCOME
1. Describe and understand the fungal infections.
2. List the classification of drugs used to treat fungal
infections.
3. Abele to demonstrate the general mechanism of
antifungal drugs.
4. Describe the adverse drug reaction of antifungal drugs.
5. Able to understand the antifungal available drugs and
dose in the market.

4
1. OVER VIEW OF FUNGAL
•Fungi are eukaryotic cells and therefore represent a more
complex and evolved organism.
• Thousands of fungal species, predominantly parasitic in
nature.
•Many are of economic importance, either because they are
useful in manufacturing other products (e.g. yeast in brewing
and the production of antibiotics) or because of the damage
they cause to crops or to foodstuffs. Approximately 50 are
pathogenic in humans.
•These organisms are present in the environment or may
coexist with humans as commensals without causing any overt
risks to health.
•However, since the 1970s, there has been a steady increase
in the incidence of serious secondary systemic fungal
infections.
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

Monera is a kingdom that contains
unicellular organisms with a
prokaryotic cell organization, (having
no nuclear membrane), such as
bacteria
eukaryotic one-celled
living organisms
distinct from
multicellular plants
and animals: protozoa,
slime molds, and
eukaryotic algae taxonomic kingdom
comprising all living
or extinct animals
Plants, also called green plants (Viridiplantae
in Latin), are living multicellular
organisms of thekingdom Plantae.
Lack chlorophyll, leaves, true stems, and
roots, reproduce by spores, and live as
saprotrophs or parasites
5Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

6

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THE FUNGI KINGDOM
Mycology - the study of fungi
fungi - singular
fungus - plural
1) fungi are eukaryotic
•they have a nuclei & mitochondria
2) they are heterotrophs
•they depend on other organisms for food
3) they are multicellular
4) they cannot move on their own
4 Main Characteristics of Fungi

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Major Types of
Mycoses
superficial
cutaneous
subcutaneous
systemic
opportunistic
1. OVER VIEW OF FUNGAL INFECTION

PATHOGENIC FUNGAI
1. CANDIDA
2. ASPERGILLUS
3. CRYPTOCOCCUS
4. HISTOPLASMA
5. PNEUMOCYSTIS
6. STACHYBOTRYS
7. MICROSPORUM
8. TRICHOPHYTON
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2. TYPES OF FUNGAL INFECTIONS

1). CANDIDA
Candida species cause infections in
individuals with deficient immune
systems. Th1-type cell-mediated
immunity (CMI) is required for clearance
of a fungal infection.
10
CANDIDA INFEC TIONSDr.K.Saminathan.M.Pharm, M.B.A, Ph.D

11
2). ASPERGILLUS
•The most common pathogenic species are Aspergillus fumigatus and
Aspergillus flavus. Aspergillus flavus produces aflatoxin which is both a
toxin and a carcinogen and which can potentially contaminate foods such
as nuts.
•Aspergillus fumigatus and Aspergillus clavatuscan cause allergic
disease.
•Some Aspergillus species cause disease on grain crops,especially
maize,and synthesize mycotoxins including aflatoxin.
•Aspergillosis is the group of diseases caused by Aspergillus. The
symptoms include fever, cough, chest pain or breathlessness.
Usually, only patients with weakened immune systems or with other lung
conditions are susceptible.

12

13
Aspergillus
fumigatus Infection
Aspergillus flavus
Infection

14
3. CRYPTOCOCCUS
•Cryptococcus neoformans can cause a severe form of meningitis
and meningo-encephalitis in patients with HIV infection and AIDS. The
majority of Cryptococcus species live in the soil and do not cause
disease in humans.
• Cryptococcus neoformans is the major human and animal pathogen.
Cryptococcus laurentii and Cryptococcus albidus have been known to
occasionally cause moderate-to-severe disease in human patients with
compromised immunity.
•Cryptococcus gattii is endemic to tropical parts of the continent of
Africa and Australia and can cause disease in non-
immunocompromised people.

15 CRYPTOCOCCUS INFECTION

16
CRYPTOCOCCUS INFECTIONS

4. HISTOPLASMA
Histoplasma capsulatum can cause
histoplasmosis in humans, dogs and
cats. The fungus is most prevalent in
the Americas, India and southeastern
Asia. It is endemic in certain areas of
the United States. Infection is usually
due to inhaling contaminated air.
17 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

18
HISTOPLASMA INFECTIONS

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5. PNEUMOCYSTIS
Pneumocystis jirovecii
(or Pneumocystis carinii) can
cause a form of pneumonia
in people with weakened
immune systems, such as
premature children, the
elderly, and AIDS patients.

20
PNEUMOCYSTIS

6. STACHYBOTRYS
Stachybotrys chartarum or "black mold"
can cause respiratory damage and
severe headaches. It frequently occurs in
houses in regions that are chronically
damp.
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7. MICROSPORUM
Microsporum canis is
a fungus that can
cause tinea capitis in
humans, and
simple ringworm in pets.
The organism's major
reservoir in companion
animals is within
domestic cats and dogs.

MICROSPORUM CANIS INFECTION

24
The fungus genus Trichophyt
on is characterized by the
development of both smooth-
walled macro-
and microconidia.
Macroconidiaare mostly
borne laterally directly on the
hyphae or on short pedicels,
and are thin- or thick-
walled, clavate to fusiform,
and range from 4 to 8 by 8 to
50 μm in size
8. TRICHOPHYTON

TRICHOPHYTON INFECTION

26
3.COMMON FUNGAL INFECTIONS AND THEIR SENSITIVITY TO
VARIOUS CLASSES OF ANTIFUNGALS

27
4. CHEMICAL STRUCTURES OF ANTIFUNGAL DRUGS

5.CLASSIFICATION OF ANTIFUNGAL
Con…
28Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

29
5.CLASSIFICATION

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6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Con…
POLYENES
IMIDAZOLES
TRIAZOLE
ALLYLAMINES
OTHER
GLUCAN
SYNTHASE
INHIBITORS
BIND TO ERGOSTEROL
AND FORM PORES
(CHANNELS)

ALLYLAMINES
IMIDAZOLES
TRIAZOLE
POLYENES
31
GLUCAN
SYNTHASE
INHIBITORSDr.K.Saminathan.M.Pharm, M.B.A, Ph.D

32

FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
POLYENES
CANDINS
GRISEOFULVIN
OTHERS
33
7. ANTI FUNGAL DRUGS MECHANISAM

34
8.MECHANISM OF AMPHOTERICIN B
Several amphotericin B molecules
bind to ergosterol in the plasma
membranes of sensitive fungal cells.
There, they form pores (channels)
that require hydrophobic
interactions between the lipophilic
segment of the polyene antibiotic
and the sterol.
The pores disrupt membrane
function, allowing electrolytes
(particularly potassium) and small
molecules to leak from the cell,
resulting in cell death.

Flucytosine enters fungal cells via a
cytosine-specific permeaseâ an enzyme
not found in mammalian cells.
Flucytosine is then converted by a series of
steps to 5-fluorodeoxyuridine 5'-
monophosphate.
This false nucleotide inhibits thymidylate
synthase, thus depriving the organism
of thymidylic acid an essential DNA
component.
Note: [Amphotericin B increases cell
permeability, allowing more 5-FC to
penetrate the cell. Thus, 5-FC and
amphotericin B are synergistic.]
9.MECHANISM OF FLUCYTOSINE

10.MECHANISM OF KETOCONAZOLE
Azoles are predominantly fungistatic.
They inhibit C-14 α-demethylase (a
cytochrome P450 enzyme), thus
blocking the demethylation of
lanosterol to ergosterol the principal
sterol of fungal membranes.
This inhibition disrupts membrane
structure and function and, thereby,
inhibits fungal cell growth.
[Note:In addition to blocking fungal
ergosterol synthesis, the drug also
inhibits human gonadal and adrenal
steroid synthesis, leading to
decreased testosterone and cortisol
production. In addition, ketoconazole
inhibits cytochrome P450]

Terbinafine inhibits fungal
squalene epoxidase, thereby
decreasing the synthesis of
ergosterol .
This plus the accumulation of
toxic amounts of squalene
result in the death of the
fungal cell.
[Note: Significantly higher
concentrations of terbinafine
are needed to inhibit human
squalene epoxidase, an
enzyme required for the
cholesterol synthetic pathway.]
11.MECHANISM OF TERBINAFINE

38
It is only fungistatic, and it causes a
number of significant drug
interactions.
Griseofulvin accumulates in newly
synthesized, keratin-containing
tissue, where it causes disruption
of the mitotic spindle and
inhibition of fungal mitosis .
Duration of therapy is dependent on
the rate of replacement of healthy
skin or nails.
Patients should not drink alcoholic
beverages during therapy, because
griseofulvin potentiates the
intoxicating effects of alcohol.
12. MECHANISM OF GRISEOFULVIN

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13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS

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14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B.

41
15. PHARMACOLOGIC PROPERTIES OF FOUR SYSTEMIC
AZOLE DRUGS

42
POLYENES

43
IMIDAZOLES

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TRIAZOLE ALLYLAMINES

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Β-3-GLUCAN SYNTHASE
INHIBITORS

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Griseofulvin Flucytosine

6.ANTIFUNGAL DRUGS

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