King Saud university Collage of pharmacyPharmacognosy dept.

Prepared by:

Fatimah BalHarith

Nouf Alwadei

Alaa Flemban

Najla Almuteiri

Supervised by: Dr. Qadria AL-Deab Dr. Areej Altaweel

 

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:

1. Superficial mycoses - limited to the outermost layers of the skin and hair.

2. 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:

3. 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.

4. Systemic mycoses due to primary pathogens - originate primarily in the lungs and may spread to many organ systems.

Classification of Mycoses: 5. 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

TreatmentPhotochemotherapy

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

Treatmentphotopheresis 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 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.)

Classification of antifungals

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

Classification of antifungals

Non polyenes antifungalsGriseofulvin: 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.

Classification of antifungalsImidazole and triazole antifungalsThe 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 LotriminThe triazoles are newer, and are less toxic and more effective * Fluconazole * Itraconazole

Classification of antifungals

AllylaminesAllylamines inhibit the enzyme squalene epoxidase,

another enzyme required for ergosterol synthesis:*Terbinafine - marketed as "Lamisil" *Amorolfine*Naftifine - marketed as "Naftin

Classification of antifungals:

EchinocandinsEchinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:AnidulafunginCaspofunginMicafungin

Structure activity relationship (SAR):

Polyene antifungal:

hydrophobic

hydrophilic

Amphtericin B

Nystatin

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.

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:

Amphtericin B & Nystatin

Mechanism of action:

Amphtericin B & Nystatin

Amphtericin B & Nystatin

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

Amphtericin BTrade names:

Fungilin®

Fungizone®

Abelcet®

AmBisome®

Fungisome®

Amphocil®

Amphotec®

Amphtericin BUses 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.

Amphtericin BPrecaution:

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 MothersPediatric Use

Amphtericin B

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

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.

Amphtericin B

Side effects: acute reaction:

fever shaking chills hypotension anorexia nausea vomiting headache dyspnea tachypnea

Side effectsNephrotoxicity (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

Amphtericin B

Drug interaction: Flucytosine Diuretics or Cisplatin  Corticosterioids Cytostatic drugs  Foscarnet, Ganciclovir, Tenofovir, Adefovir

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

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.

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.

This product is available in the following dosage forms:SuspensionTabletCapsule

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.

Brand names:Nystan Infestat Nystalocal Nystamont NystopPRECAUTION:GeneralThis 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.

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.

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.

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.

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.

Brand Names: Fulvicin P/G, Fulvicin U/F, Grifulvin V, Gris-PEG, Grisactin 250, Grisactin 500, Grisactin UltraPenicillium niciklium griseofulvum.

Spectrum of activity and Resistance:1) Effective against various species of Trichophyton,Microsporum, and Epidermophyton2) Not effective against candida and bacteria

Griseofulvin

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

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

GriseofulvinSide effects:

Skin rashesDizzinessFatigueHeadacheVomitingSwellingLoss of taste sensationTingling in the hands or feetOral thrush (yeast infection of the mouth)

Drug interactions:

drug cause

Antacids and H2 antagonists

stop its absorption.

alcohol nausea and vomiting

Warfarin

(thinning the blood less than required) because Griseofulvin increase liver

enzyme reducing the concentration of warfarin

Oral contraceptive

(increasing the chance of pregnancy) because Griseofulvin cause increase in

liver enzyme reducing the concentration of Oral contraceptive

Pharmacokinetic:Oral Diatery fat increase absorptionHalf life 9-21 hoursDemethylated 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

Contraindicatios: Systemic Lupus. Erythematosus. Porphyrias. Hepatic Failure. Not be used in pregnant

woman.

Griseofulvin

Nystatin Amphotericin B Griseofulvin

SE: Oral irritation and sensitization

Nephrotoxicity, hepatotoxicity, cardiac arrhythmias & anemia

Loss of taste sensation

Tingling ,Oral thrush

MOA: bind to ergosterol in cell memb. >>> leakage of ions >>> cell death.

Binds to keratin>>>

disrupts mitotic spindle

structure>>>defective

DNA synthesis>>>

interferes with tubulin

polymerization

ROA: topical,and orally IV oral

SOU: widely widely

Conclusion:

There is no single type of structure thus far discovered possesses Useful broad spectrum activity .

Successful treatment of human fungal disease may well require appropriate combination of vaccines, transfer factor, Antifungal drugs, and iron binding agent.