Anti Fungal Drugs

Alexandria University Collage of pharmacy Pharmaceutical Chemistry dept.

Prepared by: Mohamed Saad Gad Mohamed Rabee

Supervised by: Dr. Soaad Hawash

Fungi is: 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. 

Classification of Mycoses: Mycoses are classified according to the tissue levels initially colonized:  Superficial mycoses - limited to the outermost layers of the skin and hair.  Cutaneous mycoses - extend deeper into the epidermis, as well as invasive hair and nail diseases. These diseases are restricted to the keratinized layers of the skin, hair, and nails. The organisms that cause these diseases are called dermatophytes.

Classification of Mycoses: 

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Subcutaneous mycoses - involve the dermis, subcutaneous tissues, muscle, and fascia. These infections are chronic and can be initiated by piercing trauma to the skin, which allows the fungi to enter. Systemic mycoses due to primary pathogens - originate primarily in the lungs and may spread to many organ systems.

Classification of Mycoses: Systemic mycoses due to opportunistic pathogens - infections of patients with immune deficiencies who would otherwise not be infected. Examples of immunocompromised conditions include AIDS, alteration of normal flora by antibiotics, immunosuppressive therapy, and metastatic cancer. Examples of opportunistic mycoses include Candidiasis, Cryptococcosis and Aspergillosis. Another example of a fungal infection is Tinea versicolor: Tinea versicolor is a fungus infection that commonly affects the skin of young people 

Treatment Unlike bacteria, both fungi and humans are eukaryotes. Thus fungal and human cells are similar at the molecular level. This means it is more difficult to find a target for an antifungal drug to attack that does not also exist in the infected organism. Antifungal drugs are used to treat mycoses. Depending on the nature of the infection, a topical or systemic agent may be used. Photochemotherapy or photopheresis is a technique used at major medical centers for the treatment of mycosis

Treatment Photochemotherapy Shown is close up of surgeons' hands in an operating room with a "beam of light" traveling along fiber optics for photodynamic therapy

Treatment photopheresis is a form of apheresis in which blood is treated with photoactivable drugs which are then activated with ultraviolet light. Apheresis (Greek: "to take away") is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation.

Classification of antifungals Polyene anti fungals: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.)

Classification of antifungals Examples: * Natamycin -- 33 Carbons, binds well to ergosterol * Rimocidin * Nystatin * Amphotericin B

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Classification of antifungals 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 keratingriseofulvin 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.

Classification of antifungals 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

Classification of antifungals

Allylamines Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis: *Terbinafine - marketed as "Lamisil" *Amorolfine *Naftifine - marketed as "Naftin

Classification of antifungals: Echinocandins Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase: Anidulafungin Caspofungin Micafungin

Polyene antifungal: Structure activity relationship (SAR): hydropho bic

hydrophil ic

 Amphtericin B

 Nystatin

Polyene antifungal: Structure activity relationship (SAR): The polyene antibiotic produced by actinomycetes contain a large 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.

Polyene antifungal: 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 .

Amphtericin B & Nystatin Mechanism of action (MOA):

Amphtericin B & Nystatin

Amphtericin B Trade names: Fungilin® Fungizone® Abelcet® AmBisome® Fungisome® Amphocil® Amphotec®

Amphtericin B Uses and spectrum: Amphotericin B for injection (IV) administered primarily to patients with progressive, potentially lifethreatening 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.

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

Griseofulvin 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

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

Griseofulvin 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 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 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)