Antifungal 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 (Candida, 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. Cell membrane is made up of ergosterol. Types of fungal infections: 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 Dermatophytosis: Fungi that affect keratin layer of skin, hair and nail; e.g. Tinea pedis, rign worm infection. Candidiasis: Yeast infections caused by (Malassezia pachydermatis), oral thrush (oral candidiasis), vulvo-vaginitis, nail infection. Systemic/Deep infections: Affecting deeper tissues and organ they usually affect lungs, heart and brain leading to pneumonia, endocarditis and meningitis. 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 aspergillosis. In addition blastomycosis, histoplasmosis, 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) Salicylic acid 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. Undecylenic acid 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 antibiotics a) Amphotericin B: polyene antibiotic b) Natamycin Polyene antibiotic derived from Streptomyces 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) Griseofulvin Source: Penicillium griseofulvum Highly effective against dermatophytes d) Nystatin Source: Streptomyces noursei Not effective against dermaqtophytes Highly toxic for systemic use 4. Azoles a) Imidazoles: Ketoconzole, miconazole, clotrimozole b) Triazoles: Fluconazole, itraconazole 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 antifungals 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) Crystal violet 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 - Ketoconazole - Miconazole - Itraconazole - Terbinafine - Flucytosine Griseofulvin works only against ringworm. Nystatin works only against candida Ketoconazole, miconozole, clotrimazole work against dermatophytes + candida Fluconazole + Itraconazole Broad spectrum antifungal drug Polyene macrolide: Contains a large lactone ring with many double bonds. Polyene macrolides 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 gastrointestinal tract 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 Nephrotoxicity (tubular damage due to binding of Amphotericin B to cholesterol in the tubular cells) Electrolyte leakage ( renal acidosis) (Monitor Blood urea nitrogen, creatinine, electrolytes) Nausea Vomition Fever Headache Anemia and electrolyte disturbance Hepatotoxicity 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 Azole antifungals are broadly classified into imidazoles and triazoles Imidazole ---- ketoconazole, miconazole, clotrimazole. Miconazole, clotrimazole ---- topical use. ketoconazole ----- first orally active imidazole antifungal drug. Triazole--- 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