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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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

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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.

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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

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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 Mycosessuperficial cutaneous subcutaneous systemicopportunistic

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). 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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CANDIDA INFEC TIONSDr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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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.



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Aspergillus fumigatus Infection

Aspergillus flavusInfection



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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.



15 CRYPTOCOCCUS INFECTION



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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

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HISTOPLASMA INFECTIONSDr.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.



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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



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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




TRICHOPHYTON INFECTION


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


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4. CHEMICAL STRUCTURES OF ANTIFUNGAL DRUGS


5.CLASSIFICATION OF ANTIFUNGAL

Con…

28Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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5.CLASSIFICATION


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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)



ALLYLAMINES

IMIDAZOLESTRIAZOLE

POLYENES

31GLUCAN

SYNTHASE

INHIBITORSDr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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FLUCYTOSINE

IMIDAZOLES

TRIAZOLES

POLYENES

CANDINS

GRISEOFULVIN

OTHERS

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7. ANTI FUNGAL DRUGS MECHANISAM


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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


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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


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13. SOME ADVERSE REACTIONS OF ANTIFUNGAL DRUGS


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14. SOME ADVERSE REACTIONS OF AMPHOTERICIN B.


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15. PHARMACOLOGIC PROPERTIES OF FOUR SYSTEMIC AZOLE DRUGS


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POLYENES


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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

Health & Medicine

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view of fungal fungi

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common antifungal drugs

antifungal available

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types of fungal infections

classification of drugs