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Fungal Infections Fungi Antifungal, Antiprotozoal, Anthelmintic Drugs Dr n. med. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz Fungal infections • also called mycoses; widespread in the population (e.g. „athlete's foot” or „thrush”) • become a more serious problem (immunocompromised patients – even fetal!) • are more difficult to treat than bacterial infections • therapy of fungal infections usually requires prolonged treatment! • opportunistic infections- Pneumocystis carinii Fungi Yeasts Moulds Higher Fungi 1 Clinically important fungi may be classified into: • yeasts (e.g. Cryptococcus neoformans) • yeast-like fungi that produce a structure resembling a mycelium (e.g. Candida albicans) • filamentous fungi with a true mycelium (e.g. Trichophyton spp., Microsporum spp., Epidermophyton spp., Tinea spp., Aspergillus fumigatus ) • „dimorphic” fungi that, depending on nutritional constraints, may grow as either yeasts or filamentous fungi (e.g. Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatides) Fungal infections Superficial (topical) Systemic („disseminated”) 1. cutaneous surfaces - skin, nails, hair 2. mucous membrane surfaces - oropharynx, vagina Fungal infections Superficial Systemic • Dermatomycoses - infections • Candidiasis of the skin, hair and nails; caused by • Cryptococcal meningitis Trichophyton • Pulmonary aspergillosis Microsporum Epidermophyton • Blastomycosis Tinea capitis (scalp) • Histoplasmosis Tinea cruris (groin) • Coccidiomycosis Tinea pedis (athlete's foot) • Paracoccidiomycosis Tinea corporis (body) • Candidiasis, infections of the mucous membranes of the mouth, vagina or the skin; caused by Candida spp. 2 Ringworm an infection of the skin by a dermatophyte. Antifungal drugs • Natural (Amphotericin, Nystatin, Natamycin, Griseofulvin) • Synthetic (Azoles) • Polyenes (Amphotericin, ...) • Azoles (Ketokonazol, ...) • Echinocandins (Capsofungin, ...) • Antymetabolites (Flucytosine) • used for Systemic mycoses (Amphotericin, Fluconazole) • used for Topical mycoses (Myconazole, Clotrimazole) Amphotericin (Amphotericin B) • naturally occurring • polyene macrolide • produced by Streptomyces nodosus 3 Mechanism of action of amphotericin Activity spectrum of amphotericin • Candida albicans • Histoplasma capsulatum • Cryptococcus neoformans • Coccidioides immitis • Aspergillus • Blastomyces dermatidis • Leishmania species Pharmacokinetics of amphotericin • i.v • p.o (infections in GI tract) • topically • liposome preparation! • bound to plasma proteins • poorly penetrate BBB (!inflammation: used in cryptococcal meningitis + flucytosine) • excreted very slowly via the kidney (even 2 mths), and via the bile 4 Resistance • decreased ergosterol content of the fungal membrane • rare • synergistic combination (+ flucytosine) Side effects of amphotericin • low therapeutic index! • renal toxicity (vasoconstractive effect on afferent renal arterioles) • hypokalaemia (hypotension) • hypomagnesaemia • anemia • thrombophlebitis (heparin) • neurotoxicity (intrathecal injections) • skin rashes (topical applications) • injection: chills, fever, tinnitus, headache, vomiting Nephrotoxicity of amphotericin can be lessened by: • avoid others nephrotoxic agents (i.e. aminoglycosides) • avoid concomitant diuretic therapy • keeping patients well hydrated (saline infusion prior to amphotericin) • continuous infusion (over 24 h) 5 Nystatin • a polyene macrolide antibiotic • structure, metabolism of action ~ amphotericin • no absorbed from the GI and from the skin • I: Candida infections of the skin, mucous membranes and the GI tract. • SE: nausea, vomiting and diarrhoea Griseofulvin • produced by the mold Penicillium griseofulvin • fungistatic action, long-term treatment • binds to the fungal microtubulesinterfers cell mitosis • I: dermatophyte infections (Epidermophyton, Microsporum, Trichophyton) • p.o! (poor absorbed from GI) • inducer of Cyt. P450 • SE: GI upsets, headache, photosensitivity, allergic reactions SYNTHETIC ANTIFUNGAL AGENTS - AZOLES IMIDAZOLE (2N) TRIAZOLE (3N) • clotrimazole • itraconazole • econazole • fluconazole • fenticonazole • voriconazole • ketoconazole • miconazole The triazoles tend to have fewer side effects, better absorption, • tioconazole better drug distribution in body tissues, • sulconazole and fewer drug interactions! 6 Mechanism of action of azoles Ketokonazole • the first azole that could be given orally to treat systemic fungal infections • broad spectrum- activity • relapse is common • absorbed from GI (acidic pH) • high doses - CNS • inactivated in the liver and excreted in bile and in urine • SE: liver toxicity, GI disturbances, pruritus, gynaecomastia (inhibits testosterone synthesis) • many interactions with inducers and inhibitors of Cyt. P450 Fluconazole • p.o ; i.v • widely distribiuted (cerebrospinal fluid, ocular fluids, vaginal tissue, saliva, skin and nails) • first choice for fungal meningitis • SE: mild; nausea, headache, abdominal pain, exfoliative skin lesions or Stevens-Johnson syndrome (AIDS patients) • does not inhibit cyt. P450 and steroid synthesis (ketoconazole!) 7 Itraconazole • active against a range of dermatophytes. • p.o (absorption is variable!) • extensive metabolized in the liver • does not penetrate the cerebrospinal fluid! • inhibits cyt. P450. • SE: GI disturbances, headache, dizziness, hepatitis and liver damage, hypokalaemia, impotence, allergic skin reactions Miconazole • p.o • treating infections of GI tract. • short plasma half-life (every 8h) • therapeutic concentrations in bone, joints and lung tissue but not in the central nervous system • inactivated in the liver. • can be used topically. • SE: relatively infrequent. • inhibits cyt. P450. Other azoles • Clotrimazole Clotrimazole • Econazole • interferes with AA • Tioconazole transport into the fungus by an action on • Sulconazole the cell membrane. • active against a wide used only for topical range of fungi, application! including Candida. 8 Flucytosine • a synthetic antifungal agent • Candida infections • Mechanism of action: flucytosine 5-fluorouracil thymidylate synthetase DNA synthesis (in fungal cells!) • monotherapy resistance • politherapy recommended (+amphotericin) • i.v or p.o • SE: infrequent Terbinafine • highly lipophilic and keratinophilic. • active against a wide range of skin pathogens • nail infections! • Mechanism of action: inhibits squalene epoxidase squalene (toxic to fungi) • p.o (skin and nails) • topically (skin and mucous membranes) • metabolised in the liver by the cyt. P450 system • excreted in the urine • SE: occur in about 10% of individuals are usually mild and self-limiting • Naftifina ~ terbinafine • Amolorfina ~ topically as nail polish POTENTIAL NEW ANTIFUNGAL THERAPIES • Echinocandins: • „new generation” triazoles: Micafungin, Anidulafungin Posaconazole, Ravuconazole • Aspergillus and Candida • wide range of fungal pathogens spp., (even in AIDS patients) • SE mild, less than that seen with amphotericin. 9 Fungal infections • Drugs used for • Drugs used for treating systemic treating topical mycoses mycoses Case study Antiprotozoal drugs Protozoa are motile, unicellular eukaryotic organisms that have colonised virtually every habitat and ecological niche. 10 Protozoa AMOEBAS FLAGELLATES SPOROZOA CILIATES Entamoeba Trypanosome Plasmodium Paramecium histolytica brucei brucei falciparum caudatum Malaria Plasmodium falciparum Symptoms of malaria 11 THE LIFE CYCLE OF THE MALARIA PARASITE • The life cycle of the parasites consists of a sexual cycle, which takes place in the female anopheline mosquito, and an asexual cycle, which occurs in humans. • The mosquito, not the human, is the definitive host for plasmodia, and the only function of humans is to enable the parasite to infect more mosquitoes so that further sexual recombination can occur. THE LIFE CYCLE OF THE MALARIA PARASITE • Plasmodium falciparum malignant tertian malaria; an 48-hour erythrocytic cycle, does not have an exoerythrocytic stage • Plasmodium vivax benign tertian malaria; has an exoerythrocytic stage • Plasmodium ovale rare form of malaria; an 48-hour erythrocytic cycle and an exoerythrocytic stage • Plasmodium malariae quartan malaria; an 72-hour erythrocytic cycle, does not have exoerythrocytic cycle. 12 People living in areas where malaria is endemic may acquire a natural immunity, but this may be lost if the person is absent from the area for more than 6 months. Drugs used in the treatment of malaria: Drugs used in the treatment of malaria: 1. drugs used to treat the acute attack of malaria act on the parasites in the blood; they can cure infections with parasites (e.g. Plasmodium falciparum, P. malariae) that have no exoerythrocytic stage 2. drugs used for chemoprophylaxis act on merozoites emerging from liver cells 3. drugs used for radical cure are active against parasites in the liver 4. some drugs act on gametocytes and prevent transmission by the mosquito. 13 1. Drugs used to treat the acute attack • quinoline-methanols (e.g. quinine and mefloquine) • 4-aminoquinolines (e.g. chloroquine) • 8-aminoquinolines (e.g. primaquine) • the phenanthrene (halofantrine) • agents that interfere either with the synthesis of folate (e.g. sulfonamide – sulfadoxine; sulfones - dapsone) or with its action (e.g. pyrimethamine and proguanil) • compounds derived from Artemisia (e.g artemisinin) 2. Drugs that effect a radical cure • 8-aminoquinolines (e.g. primaquine, tafenoquine) These drugs also destroy gametocytes and thus reduce the spread of infection. 3. Drugs used for chemoprophylaxis
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