Chemotherapy: antifungal agents

49 Chemotherapy


antifungal agents





Questions



image What are the drug targets for antifungal agents?

image What are the different classes of antifungal agent?

Unlike plants, fungi do not have chlorophyll and, therefore, have evolved to live as saprophytes or parasites and reproduce by spores. Fungi can be pathogenic (Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans) or non-pathogenic (Saccharomyces cerevisiae). Yeasts are round and unicellular and multiply by budding or fission. There are also filamental forms made up of long tubes known as hyphae. A collection of hyphae is a mycelium, which is vegetative but if it is growing on a surface it can produce aerial extensions that carry spores. The dimorphic fungi can exist as yeasts or filaments and it is usually the yeast form that occurs in tissues and the filamentous form in the environment. Candida spp., however, form a mycelium in tissues. A number of drug classes have been developed that target fungal envelope (wall and membrane), microtubule assembly and DNA synthesis(Fig. 3.49.1). Fungal infections can damage tissues in several ways (Fig. 3.49.2).


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Fig. 3.49.1 Drug targets.


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Fig. 3.49.2 Tissue damage by fungal infection.



Cell envelope




Polyene macrolides


Ergosterol is the principal sterol in the fungal membrane phospholipid bilayer, whereas the mammalian membrane contains cholesterol. Amphotericin B and nystatin bind to ergosterol, causing it to change its conformation, which results in the destabilization of the fungal membrane, leading to leakage of intracellular contents and fungicidal action. Amphotericin B and nystatin have greater affinity for ergosterol (cylindrical structure than cholesterol (sigmoidal structure), which is the basis of the relative selectivity of these agents for fungal cells. Amphotericin B has a broad spectrum of activity but is poorly absorbed from the gastrointestinal tract, which may be of advantage for the treatment of gastrointestinal infections or topically for dermatological conditions. It can be administered as a slow infusion for systemic use but it is associated with nephrotoxicity; this can be minimized by changes to the formulation (e.g. encapsulating the drug in liposomes) so that the levels of amphotericin B reaching the kidney are reduced. Other side-effects include fever, chills, hypotension, vomiting and headaches. Nystatin is used topically or orally for gastrointestinal infections. Natamycin and candicidin are used in the treatment of ocular and vaginal fungal infections.


‘Azoles’ (imidazoles and triazoles) bind to the iron core ofthe haem moiety of fungal cytochrome P450 lanosterol14α-demethylase, is critical for the synthesis of ergosterol. As a result, unusual sterols are synthesized and incorporated into fungal membranes, disrupting its integrity and the function of membrane-bound enzymes. The imidazole class is mainly used for topical application, although ketoconazole has oral bioavailability. Side-effects include nausea and vomiting. Importantly, ketoconazole inhibits steroid biosynthesis, resulting in endocrine abnormalities (e.g. decreased libido, gynaecomastia, menstrual irregularities) and hepatotoxicity. It is best avoided in pregnant and breastfeeding women. Inhibition of P450 enzymes by ketoconazole increases plasma levels of certain drugs (e.g. warfarin), and vice versa. The absorption of azoles is reduced by antacids, cimetidine or rifampin and increased by thiazide diuretics. Triazoles are used for systemic infections; while some show greater selectivity for fungal cytochrome P450 (e.g. voriconazole, posaconazole), others (e.g. imidazole, fluconazole) have human P450 actions that increase levels of other drugs. Fluconazole is almost totally absorbed orally and is used in the treatment of candidiasis, cryptococcosis and other mycoses.


The enzyme squalene 2,3-epoxidase is involved in the biosynthesis of ergosterol and its inhibition by allylamines leads to squalene accumulation in the cell wall and fungal death. Terbinafine and naftifine against filamentous fungi (e.g. moulds) and very few pathogenic yeasts. Terbinafine is orally active and because of its lipophilicity concentrates in the dermis and epidermis and is used for the topical treatment of ringworm athletes foot and onychomycosis (nail infection). Side-effects include nausea, loss of taste and allergic skin reactions.


The drug amorolfine inhibits two enzymes involved late in the biosynthesis of ergosterol and is used as topical treatment as a lacquer (e.g. onychomycosis in the nails). Application directly to the skin is ineffective because nail keratin is somewhat impermeable.


The echinocardins represent a new class of antifungal agent. Capsofungin is a semisynthetic molecule from the fungus Glarea lozoyenesis. It inhibits the enzyme β(1,3)-glycan synthase and the biosynthesis of β(1,3)-glycan polysaccharides, an essential component of the fungal cell wall. This agent has a broad spectrum of activity, is fungicidal and fungistatic and is specific for fungi. Caspofungin is given i.v. and inhibits infection by filamentous fungi (Aspergillus spp.) and yeasts (Candida spp.). Side-effects include fever, headache and nausea.

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Jul 18, 2016 | Posted by in PHARMACY | Comments Off on Chemotherapy: antifungal agents

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