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Antifungal agents
This document provides information on antifungal agents used to treat fungal infections. It discusses the types of fungal infections including superficial and deep infections caused by various fungi. It then classifies and describes various antifungal drugs including polyenes like amphotericin B, azoles like fluconazole and itraconazole, allylamines like terbinafine, and antimetabolites like flucytosine. It provides details on the mechanisms of action, pharmacokinetics, clinical uses and adverse effects of these major antifungal drug classes and agents.
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Antifungal agents
- 1. RVS Chaitanya koppala Assistantprofessor, lovely professional university ANTIFUNGAL AGENTS
- 2. ANTIFUNGAL AGENTS • commonin Diabetes Mellitus, Cancer, AIDS, Pregnancy and in patients on immunosuppressive therapy such as prolonged course of corticosteriods, broad spectrum antibiotics, anticancer drugs, etc. • Treatment of fungal infections is somewhat difficult than bacterial infection because of various factors.
- 3. Antifungal Drugs • Fungalinfectious occur due to : • 1- Abuse of broad spectrum antibiotics • 2- Decrease in the patient immunity
- 4. FUNGAL INFECTIONS/CAUSATIVE ORGANISMS SUPERFICIAL MYCOSIS •Dermatophytes • Epidermophyton • Trichophyton • Microsporum • Candida • Malassezia Furfur DEEP MYCOSIS • Asperigillus • Blastomyces • Cryptococcus • Coccidioides • Candida • Histoplasma • Mucormycosis • Sporotrichosis
- 5. Types of fungalinfections • 1. Superficial : Affect skin – mucous membrane.e.g. • Tinea versicolor • Dermatophytes : Fungi that affect keratin layer of skin, hair, nail.e.g.tinea pedis ,ring worm infection • Candidiasis : Yeast-like, oral thrush, vulvo- vaginitis , nail infections.
- 6. 2- Deep infections •Affect internal organs as : lung heart brain endocarditis meningitis.
- 7. 1. ANTIBIOTICS A)Polyenes: amphotericinB, Nystatin, Hamycin, Natamycin B)Heterocyclic Benzofuran: Griseofulvin 2. Antimetabolite: Flucytosine (5-FC) 3. Azoles: A)Imidazoles (topical): Clotrimazole, Econazole, Miconazole, Oxiconazole. Systemic: ketoconazole. B)Trizoles (systemic): Fluconazole, Itraconazole, Voriconazole. Classification of Antifungal Drugs
- 8. 4. Allylamine: Terbinafine 5.Other topical agents: Tolnaftate Undecylenic acid Benzoic acid Quiniodochlor Ciclopirox olamine Butenafine Sodium thiosulfate.
- 10. Classification According toRoute of Administration • Systemic : • Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine. • Topical • In candidiasis : • Imidazoles : Ketoconazole , Miconazole. • Triazoles : Terconazole. • Polyene macrolides : Nystatin , Amphotericin-B • Gentian violet : Has antifungal & antibacterial.
- 12. Amphotericin B • AmphotericinA & B are antifungal antibiotics. • Amphotericin A is not used clinically. • It is a natural polyene macrolide • (polyene = many double bonds ) • (macrolide = containing a large lactone ring )
- 13. Pharmacokinetics • Poorly absorbedorally, is effective for fungal infection of gastrointestinal tract. • For systemic infections given as slow I.V.I. • Highly bound to plasma protein . • Poorly crossing BBB. • Metabolized in liver • Excreted slowly in urine over a period of several days. • Half-life 15 days.
- 14. Mechanism of action •It is a selective fungicidal drug. • Disrupt fungal cell membrane by binding to ergosterol , so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules ( cell death ).
- 18. Resistance to AmphotericinB • If ergosterol binding is impaired either by : • Decreasing the membrane concentration of ergosterol. • Or by modyfing the sterol target molecule.
- 19. Adverse Effects • 1-Immediate reactions ( Infusion –related toxicity ). • Fever, muscle spasm, vomiting ,headache, hypotension. • Can be avoided by : • A. Slowing the infusion • B. Decreasing the daily dose • C. Premedication with antipyretics, antihistamincs or corticosteroids.
- 20. Slower toxicity • Mostserious is renal toxicity (nearly in all patients ). • Hypokalemia • Hypomagnesaemia • Impaired liver functions • Thrombocytopenia • Anemia
- 21. Clinical uses • Hasa broad spectrum of activity • Fungicidal action. • The drug of choice for life-threatening mycotic infections. • For induction regimen for serious fungal infection. • Also, for chronic therapy & preventive therapy of relapse. • In cancer patients with neutropenia who remain febrile on broad –spectrum antibiotics.
- 22. Routes of Administration •1- Slow I.V.I. For systemic fungal disease. • 2- Intrathecal for fungal C.N.S. infections. • Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis. • 3- Local injection into the joint in fungal arthritis. • 4- Bladder irrigation in Candiduria.
- 23. Liposomal preparations of amphotericinB • Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing : • A. Nephrotoxicity • B. Infusion toxicity • Also, more effective • More expensive
- 24. Azoles • A groupof synthetic fungistatic agents with a broad spectrum of activity . • They have antibacterial antiprotozoal anthelminthic antifungal activity .
- 26. Mechanism of Action •1-Inhibit the fungal cytochrome P450 enzyme, (α- demethylase) which is responsible for converting lanosterol to ergosterol ( the main sterol in fungal cell membrane ). • 2- Inhibition of mitochondrial cytochrome oxidase leading to accumulation of peroxides that cause autodigestion of the fungus. • 3- Imidazoles may alter RNA& DNA metabolism.
- 27. Azoles • They areantibacterial , antiprotozoal, anthelminthic & antifungal. • They are fungistatic agents. • They are classified into : Imidazole group Triazole group
- 28. Imidazoles • Ketoconazole • Miconazole •Clotrimazole • They lack selectivity ,they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production. • Also, inhibit human P-450 hepatic enzyme.
- 29. Ketoconazole • Well absorbedorally . • Bioavailability is decreased with antacids, H2 blockers , proton pump inhibitors & food . • Cola drinks improve absorption in patients with achlorhydria. • Half-life increases with the dose , it is (7-8 hrs). • Inactivated in liver & excreted in bile (feces ) & urine. • Does not cross BBB.
- 30. Clinical uses Adverseeffects • Used topically or systematic (oral route only ) to treat : • 1- Oral & vaginal candidiasis. • 2- Dermatophytosis. • 3- Systemic mycoses & mucocutaneous candidiasis. • Nausea, vomiting ,anorexia • Hepatotoxic • Inhibits human P 450 enzymes • Inhibits adrenal & gonadal steroids leading to : • Menstrual irregularities • Loss of libido • Impotence • Gynaecomastia in males
- 31. Triazoles • Fluconazole • Itraconazole •Voriconazole • They are : • Selective • Resistant to degradation • Causing less endocrine disturbance
- 32. Fluconazole • Water soluble,Completely absorbed from GIT • Excellent bioavailability after oral administration • Bioavailability is not affected by food or gastric PH • Conc. in plasma is same by oral or IV route • Penetrates well BBB so, it is the drug of choice of cryptococcal meningitis • Safely given in patients receiving bone marrow transplants (reducing fungal infections) • Excreted mainly through kidney • Half-life 25-30 hours • Resistance is not a problem
- 33. Clinical uses • Candidiasis •( is effective in all forms of mucocutaneous candidiasis) • Cryptococcus meningitis • Histoplasmosis, blastomycosis, , ring worm. • Not effective in aspergillosis Side effects • Nausea, vomiting, headache, skin rash , diarrhea, abdominal pain , reversible alopecia. • Hepatic failure may lead to death • Highly teratogenic ( as other azoles) • Inhibit P450 cytochrome • No endocrine side effects
- 34. Flucytosine (5-FC) • Convertedwithin the fungal cell to 5- fluorouracil( Not in human cell ), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis. • ( Amphotericin B increases cell permeability , allowing more 5-FC to penetrate the cell, they are synergistic).
- 35. Griseofulvin • Fungistatic, hasa narrow spectrum • Given orally (Absorption increases with fatty meal ) • Half-life 24 hours • Taken selectively by newly formed skin & concentrated in the keratin. • Induces cytochrome P450 enzymes • Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure
- 36. Griseofulvin(cont.) • Inhibits fungalmitosis by interfering with microtubule function • Used to treat dermatophyte infections ( ring worm of skin, hair, nails ). • Highly effective in athlete, s foot. • Ineffective topically. • Not effective in subcutaneous or deep mycosis. • Adverse effects ; • Peripheral neuritis, mental confusion, fatigue, vertigo,GIT upset,enzyme inducer, blurred vision. • Increases alcohol intoxication.
- 37. Antifungal Drugs UsedFor Topical Fungal Infections • 1. Topical azole derivatives • 2. Nystatin& Amphotericin • 3. Terbinafine • 4. Tolnaftate • 5. Naftifine • 6. Griseofulvin
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