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21 Cards in this Set
- Front
- Back
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Polyenes
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Target ergosterol in cell membrane; they bind to it and destabilise the plasma membrane.
e.g. Amphotericin B, Nystatin |
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Azoles
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Cyt P450 3A c14a demethylase is the target; this nezyme is responsible for catalysing the production of ergosterol from lanosterol.
e.g. Clotrimazole, Fluclonazole |
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Allyamines
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Acts on enzyme catalysing production of lanosterol from squalene (squalene epoxide)
e.g. Terbinafine |
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Echinocandins
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Act on glucan synthase; forms the glucan part of the cell wall.
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5-Flucytosine
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Converted to 5-fluoruracil, which inhibits thymidylatesynthase, therefore inhibiting the production of nucleic acids.
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Problems and Solutions to Selective Toxicity
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1. Other sterols present in plasma membranes, e.g. cholesterol.
2. Human Cytochrome P450 can also be affected by azoles 3. 5-FS will also have effects on our own nucleic acid synthesis 1. We can get away with topical application of drugs; this doesn't create a systemic exposure. 2. Azoles have been refined so they bind more effectively to fungal cP450. 3. In some cases, side effects are tolerated. |
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Amphotericin B acute reactions
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Acute Reactions:
- 30 minutes post infusion, usually end by 4 hours - a result of AmB inducing prostaglandin E2 - chills, fever, SOB, aches, drop in BP - test dose then escalate, also pre dose with brufen |
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Amphotericin B nephrotoxicity
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Vasoconstriction of afferent arterioles
K+, Mg, Bicarbonate loss Decreased EPO production Over time, death of nephron units. - regular renal monitoring (GFR) - electrolyte replacement - amiloride |
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Other Amphotericin B problems
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Other:
Anorexia, nausea, vomiting Phlebitis Gradual anaemia due to reduced EPO Rarely: Thrombocytopaenia, leucopaenia, coagulopathy tinnitus, vertigo, seizures allergy and anaphylaxis |
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Lipid Formations of AmB
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These make the amphotericin B more tolerable; as the formulations circulate through the bloodstream, AmB stays attached to cholesterol. At site of inflammation, phospholipase cleaves the lipid formation, releasing AmB. There is also a more selective binding of AmB to ergosterol than to cholesterol.
Preparations include; liposomes, colloidal dispersion, ribbons. However, more AmB formation is needed for the same clinical efficacy, however it's much safer and normal AmB has been withdrawn. You get a much higher concentration of AmB in liver and spleen. However, AmB preparations do not cross the blood brain barrier. AmB new preparations are also MUCH more expensive. |
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Resistance to AmB...
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... is difficult. This requires the loss of ergosterol from the plasma membrane; this is not viable. Therefore AmB, despite its toxicity, is the ideal drug.
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Resistance to Azoles...
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- Mutation: C14 alpha protease can change, for instance.
- Efflux pumps. |
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5-Flucytosine resistance
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is rare in combination therapy. (in monotherapy, the fungus alters cell wall/membrane permeability, however all the other antifungals also affect permeability).
ALWAYS used in combination therapy. |
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Echinocandins (e.g. caspofungin)
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Target glucan synthase.
Structure of caspofungin is a glycopeptide, so cannot be given orally. Does not have a great spectrum; kills candida, aspergillis, a few others. Side effects: phlebitis, fever, headache, hepatotoxicity, haemolysis As good as AmB at salvage stage of candida infection (i.e. having already failed treatment with AmB) |
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Mycoses
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Superficial:
Dermatophytosis (skin), onychophytosis (nails), candidiasis (mucous membranes) Deep: Invasive candidiasis, aspergillosis, cryptococcosis |
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Dermatophytosis (Moulds)
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Tinea pedis - athlete's foot
Tinea cruris - crotch corporum - body manum- capitis - head Tend to be caused be moulds. |
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Tinea pedis
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Itchy, scaly, dry or wet. Especially present in patients with a predisposition to cellulitis.
Treated by topical clotrimazole or terbinafine. |
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Tinea corporis + capitis
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(ringworm)
Again, treated by topical clotrimazole. Scratching excites an inflammatory reaction, causing a kerion. |
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Dermatophytosis (Yeasts)
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Pityriasis versicolor
- variation in skin color; helped with topical clotrimazole. Mostly cosmetic. Seborrheic dermatitis (dandruff is one common form) - dandruff sufferers also have scaly growths in other locations - some anti dandruff shampoos include selenium - prescription shampoos include azoles |
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Onychomycoses (nails)
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Treated by topical terbinafine. Topical - cream or lacquer.
If the infection is a little deeper, systemic agents are required (e.g. lamisil) |
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Thrush
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Usually occurs after antibiotics
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