r r e e t t p p a CChh 9.7 1.4 Pharmacodynamics Antifungal Agents (Mode of Action of Drugs) Antifungal agents are used in the treatment of topical and systemic fungal infection They can be classified as systemic or topical antifungal agents and some are used both systemically as well as topically in the form of powder, ointment and vaginal tablets etc They are classified as in table 9.7.1 ANTIFUNGAL ANTIBIOTICS AMPHOTERICIN B It is an antifungal antibiotic obtained from Streptomyces nodosus and chemically it is an amphoteric polyene macrolide It has a highly double bonded structure The cell membrane sterol ‘ergosterol’ is found in the cell membrane of fungi and the predominant sterol of bacteria and human cell is cholesterol This antifungal antibiotic binds to ergosterol which alters the permeability of the cells by forming amphotericin-B associated pores in cell membrane, which allows the leakage of intracellular ions and macromolecules which can lead to cell death Amphotericin B has a wide spectrum of antifungal activity It is active against Histoplasma capsulatum, Cryptococcus neoformans, Candida albicans, Sporotrichum schenkii, Blastomyces brasiliensis, Coccidioides immitis, Rhodotorula, Aspergillus etc It is fungicidal at high and fungistatic at low concentration It is poorly absorbed from GIT and topically After IV administration it is widely distributed in tissues About 60% drug is metabolized in liver and excretion occurs slowly both in urine and bile Adverse effects include nausea, vomiting, headache, fever, breathlessness, anaemia, thrombophlebitis on IV administration On long term use, dose related nephrotoxicity and anaemia occurs It is used orally for intestinal candidiasis, topically for oral, vaginal and cutaneous candidiasis and hospital treatment of progressive and potentially fatal systemic fungal infections It is the gold standard of antifungal therapy Flucytosine has supraadditive action with amphotericin B if the fungi is sensitive to both It is also potentiated by rifampicin and minocycline Section 9/ Chemotherapy 344 Table 9.7.1: Classification of antifungal agents I Antifungal antibiotics Amphotericin-B (FUNGIZONE) Nystatin (MYCOSTATIN) Griseofulvin (DERMONORM) Pimaricin Hamycin II Antimetabolite Flucytosine (ALCOBON) III Imidazoles & triazoles Clotrimazole (CLOTRIN) Ketoconazole (NIZRAL) Miconazole (DAKTARIN) Econazole Itraconazole (CANDITRAL) Fluconazole (FLUZON) Also used with tinidazole (AZOSTAT) Terbinafine (LAMISIL) IV Miscellaneous agents (used topically) Tolnaftate (TINADERM) 50-100 mg QID, 200 µg to 1.5 mg/kg daily or on alternate days IV infusion, 3% topical (ear drops) lac U orally TDS, lac U topical (ointment vaginal tablet) 0.5-1.0 g/day Topical (2% cream, 25 mg vaginal tablet, 5% ophthalmic ointment) 2-5 lac U (suspension & topically as vaginal tablet and ointment) 100-150 mg/kg/day 100 mg vaginal tablet, 1% topical (lotion, cream and powder) 200 mg OD-BD orally, topical 2% ointment and shampoo 3-15 mg/kg with glucose & saline IV infusion, 1-2% topical (powder, lotion, vaginal gel, ointment & vaginal ovules) 150 mg vaginal tablet, 1% topical (cream & ointment) 100-200 mg/day (the number of days depend upon the type of infection) 400 mg on 1st day, then 200-400 mg OD, for 28 days, 250 mg OD for 6-12 wks 1% solution cream Selenium sulfide (SELSUN) Cyclopirox olamine Shampoo 1% solution, skin cream & vaginal cream Benzoic acid Sodium thiosulfate 3-5% skin ointment 20% solution Quiniodochlor 3-8% skin cream NYSTATIN It is obtained from Streptomyces noursei It has similar antifungal action as amphotericin but is highly toxic and used topically only It is effective against Candida, Histoplasma, Trichophyton, Blastomyces, Microsporum audouini etc It is indicated in Candida albicans especially oral moniliasis, monilial vaginitis, conjunctival, cutaneous and corneal candidiasis GRISEOFULVIN It is isolated from Penicillium griseofulvium It is active against Epidermophyton, Trichophyton and Microsporum causing superficial infection or dermatophytosis Antifungal Agents 345 It is not effective against fungi causing deep/systemic infection ANTIMETABOLITES It interferes with mitosis and also causes abnormal metaphase configurations Griseofulvin gets deposited in keratin and persists for weeks As it is fungistatic the newly formed keratin is not invaded by the fungus but fungus persists in already infected keratin, till it is shed off FLUCYTOSINE It is a synthetic fluorinated pyrimidine anti-metabolite which acts by its conversion to anti-metabolite 5-fluorouracil which inhibit DNA synthesis It is effective against Cryptococcus neoformans and some Candida strains and dermatiaceous moulds which cause chromoblastomycosis Adverse effects include anaemia, leukopenia, thrombocytopenia, diarrhoea, GIT disturbances and liver dysfunction It is mainly used as an adjuvant drug to amphotericin Oral absorption is irregular It is largely metabolised by methylation and excreted in urine It is ineffective topically Adverse effects include nausea, epigastric distress, vomiting, headache, peripheral neuritis, skin rash, photosensitivity, drowsiness and transient leucopenia It can cause disulfiram like reaction It is indicated in fungal infections of skin, scalp and nails, tinea of hand and beard and athlete’s foot PIMARICIN It is obtained from Streptomyces notalensis and it is found effective against Trichophyton violaceum, Trichomonas vaginalis and Aspergillus fumigatus It is used as eye ointment in keratitis due to Fusarium and Cephalosporium and as an inhalation in bronchopulmonary aspergillosis and candidiasis HAMYCIN It is obtained from Streptomyces pimprina and effective against blastomycosis, cryptococcosis, vaginal and cutaneous candidiasis, Trichomonas vaginitis and Aspergillus otomycosis Adverse effects include diarrhoea, eosinophilia, nephrotoxicity and rise in SGOT levels after oral administration in the treatment of blastomycosis in man IMIDAZOLES & TRIAZOLES CLOTRIMAZOLE Clotrimazole, is an imidazole derivative and has a broad antimycotic spectrum of action in vivo, which includes dermatophytes, yeasts, moulds etc Clotrimazole acts against fungi by inhibiting ergosterol synthesis Inhibition of ergosterol synthesis leads to structural and functional impairment of the cytoplasmic membrane In addition, it also acts on Trichomonas vaginalis, gram positive microorganisms (streptococci/staphylococci) and gram negative microorganisms (Bacteroides/ Gardnerella vaginalis) It is useful as topical application It is indicated in infections of the genital region (vaginitis) caused by fungi (mostly Candida) and superinfections caused by clotrimazole sensitive bacteria; infectious leucorrhoea caused by yeast fungi 346 It is well tolerated but some patients reported skin reactions including burning, stinging or redness KETOCONAZOLE It is orally effective broad spectrum imidazole antifungal drug It is useful in both dermatophytosis and deep mycosis Oral absorption is facilitated by gastric acidity It is highly protein bound, metabolised in liver and metabolites are excreted in urine and faeces Its spectrum is similar to that of miconazole and is more active against Coccidioides Adverse effects include gastric irritation, nausea, vomiting, headache, paresthesia, rash, hair loss, allergic reaction and gynecomastia MICONAZOLE It has broad spectrum antifungal and antibacterial activity and is effective against Cryptococcus, Blastomyces, dermatophytes, Microsporum, Coccidioides and Candida Used topically as ointment, lotion, gel, ear drop and vaginal gel Adverse effects include fever, chills, allergic reaction and even anaphylaxis It is indicated in vulvovaginal candidiasis, Trichomonas vaginitis, otomycosis, tinea and Pityriasis versicolor ECONAZOLE It is similar to clotrimazole and is effective in dermatophytosis, otomycosis and oral thrush It causes local irritation ITRACONAZOLE It is a triazole antifungal drug closely related to ketoconazole and is meant for oral use It is very effective in a wide range Section 9/ Chemotherapy of superficial and deep seated fungal infections It impairs the synthesis of ergosterol in fungi After oral administration, it is widely distributed in the body CSF and saliva contain negligible amounts of the drug It is extensively metabolised in liver and the metabolites are excreted in urine It is indicated in dermatophytoses, tinea versicolor, onychomycoses, oropharyngeal candidiasis, cutaneous candidiasis, chronic mucocutaneous candidiasis, oculomycoses; systemic mycoses like cryptococcosis, candidiasis and aspergillosis; subcutaneous mycoses like sporotrichosis and chromomycosis Adverse effects include nausea, vomiting, skin rash, depression, dizziness, vertigo and loss of libido, hypokalemia and hypertriglyceridemia FLUCONAZOLE It has broad range of antifungal activity It is well absorbed orally (94%) It is primarily excreted unchanged in urine Fungicidal concentration is achieved in nail, saliva and vagina and also penetrates brain Adverse effects include nausea, vomiting, headache, abdominal pain, diarrhea and skin rash It is indicated in mucosal candidiasis, systemic candidiasis, crypttococcosis, prophylaxis of fungal infections following cytotoxic chemotherapy or radiotherapy; maintenance to prevent relapse of cryptococcal meningitis in patients with AIDS; sporotrichosis, histoplasmosis and vaginal candidiasis Antifungal Agents TERBINAFINE It is a synthetic allylamine derivative, which exerts its antifungal effect by inhibiting squalene epoxidase leading to deficiency of ergosterol and corresponding accumulation of squalene which causes fungal cell death It is well absorbed from the GI tract, widely distributed in body It is strongly plasma protein bound It is metabolised in the liver to inactive metabolites which are excreted in the urine Adverse effects are irritation, burning, itching and dryness on topical application Oral intake causes gastric upset, rash, taste disturbance and hepatic dysfunction Terbinafine is used in the treatment of dermatophytoses especially onchomycosis by oral therapy Also useful in tinea and pityriasis versicolor MISCELLANEOUS AGENTS Tolnaftate is effective in tinea cruris and tinea corporis Used in the form of solution 347 and cream used topically Not useful in candidiasis and other types of superficial mycoses Adverse reaction includes local irritation Selenium sulfide is used as shampoo and used in the treatment of scalp fungal infection Cyclopirox olamine is used in the treatment of tinea infections, dermal and vaginal candidiasis Benzoic acid has got antifungal and anti-bacterial activity and used in combination with salicylic acid (Whitfield’s ointment) Salicylic acid by its keratolytic action helps to remove the infected tissue and promotes the penetration of benzoic acid into the lesion Sodium thiosulfate is effective against Malassezia furfur Quiniodochlor is found effective against dermatophytosis, infected eczema and seborrhoeic dermatitis Orally it is used as luminal amoebicide ... number of days depend upon the type of infection) 400 mg on 1st day, then 200-400 mg OD, for 28 days, 250 mg OD for 6-12 wks 1% solution cream Selenium sulfide (SELSUN) Cyclopirox olamine Shampoo... metaphase configurations Griseofulvin gets deposited in keratin and persists for weeks As it is fungistatic the newly formed keratin is not invaded by the fungus but fungus persists in already... anti-metabolite 5-fluorouracil which inhibit DNA synthesis It is effective against Cryptococcus neoformans and some Candida strains and dermatiaceous moulds which cause chromoblastomycosis Adverse