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Home , Amphotericin B, Crystal violet, Natamycin, Undecylenic acid

Drugs

 Antifungal or antimycotic drugs are those agents used to treat diseases caused by fungus.  Fungicides are drugs which destroy fungus and fungistatic drugs are those which prevent growth and multiplication of fungi. Collectively these drugs are often referred to as antimycotic or antifungal drugs.

General characteristics of fungus:  Fungi of medical significance are of two groups:  Yeast Unicellular (, Crytococcus)  Molds Multicellular; filamentous consist of hyphae (Aspergillus, Microsporum, Trichophyton)  They are eukaryotic i.e. they have well defined nucleus and other nuclear materials.  They are made of thin threads called hyphae.  The hyphae have a cell wall (like plant cells) made of a material called chitin.  The hyphae are often multinucleate.  They do not have chlorophyll, can’t make own food by photosynthesis, therefore derive nutrients by means of saprophytic or parasitic existence.  is made up of .

Types of fungal :

Fungal infections are termed as mycoses and in general can be divided into:

Superficial infections: Affecting skin, nails, scalp or mucous membranes; e.g. Tinea versicolor

: Fungi that affect keratin layer of skin, hair and nail; e.g. Tinea pedis, rign worm .  : Yeast infections caused by (Malassezia pachydermatis), oral thrush (), vulvo-vaginitis, nail infection.

Systemic/Deep infections: Affecting deeper tissues and organ they usually affect lungs, heart and brain leading to pneumonia, endocarditis and . Systemic infections are associated with immunocompromised patients, these diseases are serious and often life threatening due to the organ involved.

 Some of the serious systemic fungal infections in man are candidiasis, cryptococcal meningitis, pulmonary .  In addition , , coccidiomycosis and paracoccidiomycosis are common fungal infections which often occur as primary infections.  In animals Aspergillus fumigatus causes “brooder pneumonia” in chickens and mycotic abortion” in cattle.  Superficial fungal infections are classified into dermatomycosis and candidiasis.  Ringworm (dermatomycosis or dermatophytosis) is the most common fungal skin disease of man and animal.  The dermatophyte which cause ringworms in animals and birds belong to two genera Trichophyton and Microsporum  Followings are the species of Trichophyton and Microsporum affecting animals.

Trichophyton verrucosum var. discoides - causes outbreaks in cattle and is transmissible in man, also occasionally occurs in horses, dogs and goats.

T. mentagrophytes - Dogs, cats.

T. equinum - Horses.

T. gallinae - Causes favus in poultry.

Microsporum canis - Causes ringworm in dogs and cats

Microsporum equinum - Occasional outbreaks in horse.

These ringworm are transmissible to man and Microsporum spp. is contagious.

Classificaiton of antifungal drugs

1. Organic acids and their salts a) Benzoic acid Action: Fungistatic and bacteriostatic b) Action: Antipyretic and keratolytic

Preparation: Whitfield’s ointment: Benzoic acid 6 parts, salicylic acid 3 parts, Vaseline 91 parts. Use: Ringworm/Superficial mycotic infection. 2.  It is a yellow liquid having fungistatic property.  Long exposure with high concentration may have fungicidal effect.  High concentrations of the acid have irritant effect so zinc or copper salts of the acid are used to minimize the effect.  It is effective against Microsporum spp. 3. Antifungal a) : polyene b)  Polyene antibiotic derived from nataliensis  Effective against dermatophytes, bovine yeast mastitis and mycotic keratitis  In mastitis caused by Candida spp. 20 ml of 2.5% solution of natamycin is infused into affected teat once daily for 3 days.  In ringworm used as suspension containing 1 mg/ml.  Animals should be treated indoor or in evening to avoid inactivation which occurs in sunlight c)  Source: griseofulvum  Highly effective against dermatophytes d)  Source: Streptomyces noursei  Not effective against dermaqtophytes  Highly toxic for systemic use

4. a) : Ketoconzole, , clotrimozole b) : , Miconazole nitrate:  2% cream or 1% lotion usually recommended or ringworm of cat or dog.  Action: Penetrates chitin of the fungal cell wall with increased permeability. 5. Miscellaneous a) Dichlorophen  Besides its taenicide action, it is a useful fungicide  2% ointment or alcoholic solution against dermataophytes Action: Fungicidal Use: Cattle ringworm

b) Monosulfirum: Fungicidal( Ear preparation) c) Copper sulfate  Strongly fungicidal and has astringent and caustic property  5% ointment or 1-2% aqueous solutions Use: Cattle ringworm (Farm animal practice) Action: Fungicidal d)  Used as 1% alcoholic solution Use: Ringworm Action: Fungistat

Classification of antifungal drugs based on their site of/ route of application:

i. Topical agents - Benzoic acid - Salicylic acid - Undecylenic acid - Natamycin - Nystatin - Dicholophen - Monosulfiram - Copper sulfate - Crystal violet - Azoles: Miconazole, Clotrimozole ii. Systemic agents a) Antifungal antibiotics - Amphotericin B - Griseofulvin b) Synthetic antifungal agents: Broad spectrum fungistatic agents - Fluconazole - - Miconazole - Itraconazole - -

Griseofulvin works only against ringworm.

Nystatin works only against candida

Ketoconazole, miconozole, work against dermatophytes + candida

Fluconazole + Itraconazole Broad spectrum antifungal drug

Polyene : Contains a large lactone ring with many double bonds. Polyene include (these are also antifungal antibiotic) amphotericin B, natamycin, nystatin (all are natural)

Amphotericin B

 Amphotericin A and B are polyene antifungal antibiotics  Amphotericin A is not used clinically  It is a natural broad spectrum antifungal antibiotic  Both amphotericin A and B are natural fermentation product of the actinomycetes Streptomyces nodosus  It is an amphoteric compound consists of a large macrolide ring with a hydrophobic conjugated double bond chain and a hydrophilic hydroxylated carbon chain and attached sugar.  It is a yellowish powder and insoluble in water and somewhat unstable.

Mechanism of action:

Amphotericin B

Binds tightly to ergosterol in fungal cell membrane

Forms ‘pores’ and ‘channels’ in the membrane

Increase permeability of cell membrane

Leakage of intracellular contents

Death of the fungi (Fungicidal)

Pharmacokinetics:

 Poorly absorbed from the GI tract, hence is not suitable orally for systemic infection.  Effective for fungal infection of and oral yeast infection.  For systemic infection given as IV  Highly bound to plasma protein; widely distributed to various tissues.  Does not cross Blood Brain Barrier (BBB)  Metabolized in liver  Excreted slowly in urine over a period of several days.

Adverse effects: Most toxic of all antifungal agents

(tubular damage due to binding of Amphotericin B to cholesterol in the tubular cells) Electrolyte leakage ( renal acidosis) (Monitor Blood urea nitrogen, creatinine, electrolytes)   Vomition   Anemia and electrolyte disturbance 

Use: Effective against Crytococcus spp., Candida spp., Aspergillus spp., Blastomyces and Histoplasma capsulatum

Griseofulvin

 Narrow spectrum fungistatic agent  Source: Penicillium griseofulvum  Used orally for dermatophytic infections  It is colorless, slightly bitter and virtually insoluble in water  It is not effective topically  It gets concentrated in keratinized tissues such as skin,hair,nail

Mechanism of action: Griseofulvin interacts with microtubules and interferes with mitosis.

Griseofulvin

Interacts with polymerized microtubules

Disrupt the mitotic spindle

Spindle poison, thus griseofulvin inhibits fungal mitosis

Pharmacokinetics:

 It is available only as an oral preparation.  Oral absorption depends on particle size, the less the particle the more/rapid the absorption. Microsized preparations are 25-70% absorbed.  Distributed to keratin of skin, hair and nail. the drug is bound tightly to keratinocytes and remains in the skin until these cells are shed.  Metabolized in liver (6 times faster in animals than in human). For this reason animal dose is higher than human dose.  Excreted through urine.

Adverse effects: Mainly occurs in cats.

 Extremely teratogenic in cats  Leucopenia  Anemia  Headache  Malaise  Rashes

Use: Ringworm/dermatophytic (Microsporum, Trichophyton, Epidermatophyton) infection

Dose: Small animals: 25 mg/kg at every 12 hours for 4 weeks

Azoles

antifungals are broadly classified into imidazoles and triazoles  ---- ketoconazole, miconazole, clotrimazole.  Miconazole, clotrimazole ---- topical use.  ketoconazole ----- first orally active imidazole antifungal drug.  --- Fluconazole, itraconazole  Imidazoles are less specific than triazoles and produce side effects due to inhibition of CYP- 450.  Both of them are structurally related compound, having similar mechanism of action and antifungal spectrum.  Broad spectrum fungistatic agents.

Mechanism of action: Inhibit synthesis of ergosterol of fungal cell membrane by inhibiting 14∞-demethylase enzyme.

Ketoconazole

 Most popular antifungal agent in veterinary medicine  It is effective orally as well as topically (skin and tissue distribution) for various fungal infections such as candidiasis dermatophytosis and deep  It is the most toxic among azoles hence used commonly by topical route in candida and dermatophytic infections

Mechanism of action: Same as other azoles

Pharmacokinetics: It is orally effective, acidic environment favours the absorption of ketoconazole, hence its is reduced by H2 blockers, proton-pump inhibitors and antacids.

 Highly bound to plasma protein.  It distributes throughout the skin and subcutaneous tissues, making it suitable for treatment of superficial and systemic fungal infections.  Metabolized in liver and excreted mainly in feces.

Adverse effects:   Nausea  Vomition  Hepatotoxicity  Hypersensitivity reactions

Use: Used against dermatophytosis, candidiasis, histoplasmosis, blastomycosis.

Dose: For dermatophytosis in cats 10 mg/kg/day For candidiasis in cats 10 mg/kg/day for 6-8 weeks For canine blastomycosis, histoplasmosis, dose is 10-12 mg/kg at every 12 hours.