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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 9-253 COMMON FUNGAL INFECTIONS AND THEIR
SENSITIVITY TO VARIOUS CLASSES OF ANTIFUNGALS26
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.
1. OVER VIEW OF FUNGAL
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
7
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
1. OVER VIEW OF FUNGAL
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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Major Types of Mycosessuperficial cutaneous subcutaneous systemicopportunistic
1. OVER VIEW OF FUNGAL INFECTION
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
1). CANDIDACandida species cause infections in individuals with deficient immune systems. Th1-type cell-mediated immunity (CMI) is required for clearance of a fungal infection.
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2. TYPES OF FUNGAL INFECTIONS
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.
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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Aspergillus fumigatus Infection
Aspergillus flavusInfection
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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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.
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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.
2. TYPES OF FUNGAL INFECTIONS
17 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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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.
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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.
2. TYPES OF FUNGAL INFECTIONS
21Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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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.
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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The fungus genus Trichophyton 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
2. TYPES OF FUNGAL INFECTIONS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
26
3.COMMON FUNGAL INFECTIONS AND THEIR SENSITIVITY TO VARIOUS CLASSES OF ANTIFUNGALS
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
Con…
POLYENES
IMIDAZOLESTRIAZOLE
ALLYLAMINES
OTHER
GLUCAN
SYNTHASE
INHIBITORS
BIND TO ERGOSTEROL AND FORM PORES (CHANNELS)
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
6.SITES OF ACTION OF COMMON ANTIFUNGAL DRUGS
ALLYLAMINES
IMIDAZOLESTRIAZOLE
POLYENES
31GLUCAN
SYNTHASE
INHIBITORSDr.K.Saminathan.M.Pharm, M.B.A, Ph.D
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
POLYENES
CANDINS
GRISEOFULVIN
OTHERS
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7. ANTI FUNGAL DRUGS MECHANISAM
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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.
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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
35 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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]
36 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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
37 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D
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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
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D