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Antifungal agents Africa college pre.pdf
- 1. Antifungal agents 1 Fungusincludes yeast, mold and mushrooms Some species are parasitic in nature Mycosis – diseases caused by fungus Common not only as primary disease but also due to: • Widespread use of broad-spectrum antibiotics • The use of immunosuppressant or cancer chemotherapy • The spread of AIDS Fungal infections: systemic or superficial
- 2. Antifungal agents… 2 Systemic antifungalagents Amphotericin B Flucytosine Azoles • Imidazoles: Ketoconazole • Traizoles: Itraconazole, fluconazole and voriconazole Griseofulvin, Terbinafine – AKA systemic antifungals for mucocutaneous infections
- 3. Antifungal agents… 3 Topical antifungalagents Imidazoles: clotrimazole, miconazole, ketoconazole Nystatin, amphotericin B Benzoic acid and salicylic Acid • An ointment containing benzoic and salicylic acids is known as Whitfield's ointment • Combines the fungistatic action of benzoate with the keratolytic action of salicylate • It contains benzoic acid and salicylic acid in a ratio of 2:1 (usually 6% to 3%) and is used mainly in the treatment of Tinea pedis
- 4. 4 Amphotericin B Polyenemacrolide antibiotic Insoluble in water but has special formulations for iv infusion Has very broad spectrum antifungal activity Mechanism of action • Bind to ergosterols in cell membrane lining • Allow K+ & Mg2+ to leak out • Cell death
- 5. Amphotericin B… 5 Pharmacokinetics Poorlyabsorbed from GIT, given orally only if there is fungal infection of GIT For systemic infection, it is given by slow IV infusion Can also be given topically Poorly crosses BBB but increase passage during inflammation • Amph. B is used with flucytosine to treat Cryptococcal meningitis
- 6. Amphotericin B… 6 Therapeutic use Meningitis caused by Coccidioides (IV/intrathecal infusion ) Intravenous administration of amphotericin B is the DOC • Initial treatment of cryptococcal meningitis • Mucormycosis , severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis • Pts not responding to azole therapy of invasive aspergillosis, extracutaneous sporotrichosis, trichosporonosis and other fungal sepsis
- 7. Amphotericin B… 7 Therapeutic use… Mycotic corneal ulcers and keratitis (topical drops or direct subconjunctival injection) Fungal arthritis (local injection directly into the joint)
- 8. Amphotericin B… 8 Untoward effects Amph. B has low TI Infusion related • Fever, chills, hypotension ( acute reactions) • Can be decreased by Slowing the infusion or decreasing the daily dose Premed. with antipyretics, antihistamines, glucoco’ids, meperidine Nephrotoxicity – the commonest and serious Hypokalemia→1/3 of pts require KCl on prplonged therapy Renal tubular acidosis, magnesium loss, azotemia Headache, N, V, malaise, weight loss, and phlebitis(Comm.) Anaemia, thrombocytopenia or mild leukopenia (rare)
- 9. 9 Flucytosine (5-fluorocytosine) Has antifungalactivity against Cryptococcal neoformans, Candida species and chromoblastomycosis Mechanism of action • First metabolized in fungal cells to 5-fluorouracil • Then to 5-fluorodeoxyuridine monophosphate and fluorouridine triphosphate Inhibit DNA and RNA synthesis Mammalian cells can't convert flucytosine to 5-fluorouracil
- 10. 10 Flucytosine… Pharmacokinetics • Absorbed welland rapidly after oral administration • Widely distributed in the body including CSF • 80%excreted unchanged in urine • Dose adjustment is necessary in renal dysfunction
- 11. Flucytocine… 11 Therapeutic use • Usuallyused in combination with amphotericin B in treatment of cryptococcal meningitis Untoward effects • Bone marrow suppression (most common) • Rash, nausea, vomiting, diarrhea and severe enterocolitis • Toxicity is more frequent in AIDs patients, in renal failure and in high dose
- 12. 12 Imidazoles andTriazoles Bothclasses have the same MOA and similar antifungal spectrum Triazoles have less effect on human sterol synthesis Imidazoles Triazoles Clotrimazole Itraconazole Ketoconazole Fluconazole Miconazole Voriconazole
- 13. Imidazoles andTriazoles… 13 Syntheticfungistatic agents with a broad spectrum of activity • Many Candida species, Cryptococcus neoformans, blastomycosis, coccidioidomycosis, histoplasmosis, dermatophytes • Aspergillus infection :Itraconazole and voriconazole • Candida krusei and the agents of mucormycosis are resistant All azoles are contraindicated during pregnancy
- 14. Imidazoles andTriazoles… 14 Mechanism ofaction • Inhibit 14--sterol demethylase, a microsomal CYP450 enzyme • Impairs the biosynthesis of ergosterol for cytoplasmic membrane Methylsterols may disrupt the close packing of acyl chains of phospholipids Impair the functions of certain membrane-bound enzyme such as ATPase and enzymes of the electron transport system Inhibit growth of the fungi
- 15. Imidazoles andTriazoles… 15 Ketoconazole Has greater propensity to inhibit mammalian CYP450 enzymes Non-selective to fungal enzymes Given orally to treat systemic fungal infections Need acidic media for absorption It is toxic (low TI) and relapse is common Synergy with flucytosine against candida, but antagonizes Amph.B
- 16. Imidazoles andTriazoles… 16 Ketoconazole… Therapeutic uses •Has been replaced by itraconazole for treatment of all mycosis ADRs: • GI distress • Endocrine effects: gynaecomastia, decreased libido, impotence and menstrual irregularities Inhibition of androgen and adrenal steroid synthesis • Hepatic dysfunction (serious)
- 17. Imidazoles andTriazoles… 17 Itraconazole Availablein oral and IV formulation Absorption is increased by food and low gastric PH Inhibit hepatic microsomal enzymes to a lesser degree than ketoconazole It does not affect mammalian steroid synthesis Like ketoconazole, penetrates to CSF poorly
- 18. Imidazoles andTriazoles… 18 Itraconazole… Therapeutic use •Blastomycosis, histoplasmosis, and sporothrix(azole of choice ) • Aspergillosis (azoles DOC- voriconazole) • Dermatophytoses and onychomycosis (used extensively) Adverse effects • Nausea and vomiting • Rash, hypokalemia, hypertriglyceridemia • hepatotoxicity
- 19. Imidazoles andTriazoles… 19 Fluconazole •Distinguished from the other azoles by its high oral bioavi. and good CSF penetration • Lack of the endocrine side effects of ketoconazole • Has the least effect of all azoles on hepatic microzomal enzm. • It has the widest therapeutic index of azoles, permitting more aggressive dosing in variety of fungal infections
- 20. Imidazoles andTriazoles… 20 Fluconazole… Therapeutic uses • Azole of choice for the treatment and secondary prophylaxis of Cryptococcal meningitis • Candidemia • Coccidioidomycosis • The most commonly used agent for mucocutaneous candidiasis •Prophylactically used to reduce fungal infection in bone marrow transplant recipients and AIDS patients
- 21. Imidazoles andTriazoles… 21 Voriconazole •Available in intravenous and oral formulation • Well absorbed orally, with bioavailability of >90% • Similar to itraconazole in its spectrum of action Excellent activity against candida species including fluconazole resistant C. krusei Less toxic and probably more effective than amphotericin b in the treatment of invasive aspergillosis ADRs: rash, elevated hepatic enzyme; visual disturbances (blurring, change in color vision or brightness; resolve with in 30 minutes of adm.)
- 22. Echinocandins 22 • Caspofungin, micafungin,anidulafungin • They are large cyclic peptides linked to a long-chain fatty acid • Available only for intravenous administration • Active against candida and aspergillus, but not C. neoformans • Water soluble and Highly protein bound drugs • Plasma half life: caspofungin(9-11 hrs), micafungin(11-15hrs) , anidulafungin (24-48 hrs) ADRs: phlebitis at the infusion site; Histamine-like effects with rapid infusions
- 23. Imidazoles andTriazoles… 23 Topical imidazoles Clotrimazole, miconazole, ketoconazole Clinical indication • Dermatophytic infec. Including T.corporis, T. pedis ,T.cruris, and T.versicolor (creams) • Mucocutaneous candidiasis • Oral thrush (oral clotrimazole lozenge)
- 24. 24 Griseofulvin Anarrow-spectrum antifungal agent; fungistatic It is a potent inducer of CYP450 enzyme, fatty food its absorption Mechanism of action •Binding to fungal microtubules to disrupt the mitotic spindle →inhibit mitosis Therapeutic uses • Only used for the treatment of dermatophytosis (orally adm.) Trichophyton, Microsporum and Epidermophyton •It has largely been superseded by other drugs (itraconazole and terbinafine)
- 25. 25 Griseofulvin… Adverse drugreactions Allergic reactions- rashes, fever, serum sickness GI upsets, headache Photosensitivity Hepatotoxicity The drug should not be given to pregnant women
- 26. 26 Terbinafine Usedfor the treatment of dermatophytoses, especially onychomycosis, Tinea cruris, Tinea corporis Highly lipophilic, keratinophilic fungicidal Mechanism of action • Interferes with ergosterol biosynthesis, it inhibits the fungal enzyme squalene epoxidase → accumulation of the sterol squalene, which is toxic to the fungus More effective than griseofulvin and itraconazole ADRs: GI upset, headache, or rash
- 27. 27 Nystatin Polyene macrolideantibiotic Mechanism of action similar to amphotericin B Not absorbed from GI, skin or vagina Useful only for Candida infection Preparation are available for cutaneous, vaginal or oral administration • Powder, ointment and cream preparation Hyper keratinized or crusted skin lesions do not respond Adverse effect is uncommon
- 28. 28 Topical allylamines Terbinafineand naftifine Available as creams Effective for treatment of tinea cruris and tinea corporis