Antifungal agents Fungi Also known as mycoses Very large and diverse group of microorganisms Of...
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![Page 1: Antifungal agents Fungi Also known as mycoses Very large and diverse group of microorganisms Of major two types: yeasts and molds. Mycotic Infections:](https://reader036.fdocuments.us/reader036/viewer/2022062515/56649cac5503460f9496e783/html5/thumbnails/1.jpg)
Antifungal agents FungiAlso known as mycosesVery large and diverse group of microorganismsOf major two types: yeasts and molds.Mycotic Infections:
CutaneousSubcutaneousSuperficialSystemic:
Can be life-threateningUsually occur in immunocompromised host
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Targets for Antifungal agents- Generally these targets should be different from mammalians.- Both human and fungi are eukaryotic, so not much difference
could be found.
- The most important difference is the presence of cell wall for fungi that is not found in humans.
- Other targets are:- Inhibitors of DNA synthesis.- Disruption of mitotic spindle.- Interfere with metabolism.
- The most exploited difference is the nature of sterols:- Important components of cell membrane for proper function of
cell membrane enzymes and ion transporter proteins.
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Targets for Antifungal agents- Mammalians contain cholesterol while fungi posses
ergosterol.
- The difference is in the side chain of ergosterol which is more flat compared to cholesterol;
- A difference that is responsible for providing selectivity for the majority of antifungal agents.
Cholesterol
Ergosterol
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Polyene membrane disrupters- Polyenes: macrocyclic lactones with distinct hydrophilic and
lipophilic regions.- Produced from Streptomyces species- Hydrophilic: alcohol, carboxylic acids, sugar.- Lipophilic: contain a pharmacophore of 4-7 conjugated double
bonds.
- The number of the double bonds correlate directly to activity and inversely to toxicity.
- Amphotericin is 10X more active which can be taken systemically.
- Mechanism of action: have affinity to ergosterols containing membranes, then inserted in the cell membrane, disrupts its function, leak of cell components.
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Amphotericin
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Polyene membrane disrupters1- Nystatin:
- A tetraene agent that used topically.- No oral absorption, so used orally for mouth and GIT infections.
2- Amphotericin B: - Heptaene derivative with low enough toxicity for I.V use, but still toxic drug used with caution.
- It does not cross BBB, so used intrathecally of brain fungal infections.
- The main side effect is nephrotoxicity, reduced by formulation change.
- Liposomal encapsulation was found to target infected tissues as the capillary size at the infected areas is larger, so release the drug specifically at that area.
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Nystatin
Amphotericin nephrotoxicity
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Ergosterol Biosynthesis inhibitorsA- Azoles:
- The largest group of antifungal agents.- Some used topically and others used systemically.- some are orally bioavailable with broad spectrum properties.
- SAR:- 5-membered ring with 2-3 Ns.- side chain attached to N.- At least has one aromatic ring.
- Mechanism of action: - Act by inhibiting ergosterol synthesis by inhibiting
CYP450 14-α-demethylase, where the basic nitrogen N3 of the drug bind to heme iron of the enzyme blocking the active site.
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R R
CO2H
CO2 RFe-Cyt P-450
Lanosterol Carboxylate Ergosterol
NN
NN Fe-Cyt P-450
Fe-Cyt P-450
Mechanism of action of Azoles
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Ergosterol Biosynthesis inhibitors
- Inhibition will lead to accumulation of sterols with extra methyl group.
- This new sterol structure does not have the shape and physical properties of the normal ones, leading to permeability changes.
- Selectivity to mammalian C450 compared to the fungal one is 1:1000, and even, most of azoles considered mammalian C450 inhibitors which lead to serious drug-drug interactions in some cases.
- Systemic azoles are : Ketoconazole, Itraconazole, Fluconazole and voricanazole.
- Non-systemic azoles are : Clotrimazole, Oxiconazole and miconazole.
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Ergosterol Biosynthesis inhibitors
1. Ketoconazole:
- Imidazole derivative, that is orally active for systemic infections.
- Depends mainly on low stomach pH for absorption.
- Inhibit C450 causing serious drug-drug interactions.
- All its metabolites are inactive and mainly used topically.
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Ergosterol Biosynthesis inhibitors
Ketoconazole Metabolism:
- Deacylation.- Aromatic hydroxylation.
HydroxylationBinds heme active site
Deacylation
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Ergosterol Biosynthesis inhibitors2- Itraconazole:
- Triazole derivative.- Oral bioavailability depend on food and stomach pH.- highly interfere with liver enzymes (serious drug drug interactions).
3- Fluconazole: - Equal bioavailability, oral and I.V.- Could cross BBB (Why?).- Weak inhibitor to some liver enzymes.
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Ergosterol Biosynthesis inhibitorsB- Allylamines:
- They have limited spectrum of activity which is only used for dermatophytes.
- Includes: Naftifine, Terbinafine, and Tolnaftate
- Mechanism of action: inhibit squalene epoxidase, - leading to build up of squalene that it self is toxic compound. - and also lead to reduction of sterol levels in cell membrane, leading to cell lysis.
- Mammalian squalene epoxidase is less sensitive to these drugs.
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O
HO HO
Ergosterol
Squalene
Epoxidase
Steps
Lanosterol
Steps
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Ergosterol Biosynthesis inhibitors
-Terbinafine:- Topical and Oral.- Active against many dermatophytes.- Highly lipophilic.- Extensively metabolized.
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Ergosterol Biosynthesis inhibitors
C- Morpholines: - Amorolfine:
- The only drug of this class, used topically.- Act on Δ14 reductase enzyme, and Δ8, Δ7 isomerase enzymes.- produce non-similar compounds with different
physical properties, leading to cell leakage.
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Miscellaneous mechanism of actions
- Flucytosine:- Powerful agent for systemic infections.- Taken up by fungal cells and interferes with DNA synthesis- Prodrug to produce 5-flurouracil.
- Griseofulvin: - Orally taken for superficial infections.
- Not used topically.
- Bind to protein tubulin.
- Interfere with cell division.
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N
NH
NH2
F
O
HN
NH
O
F
O
HN
N
O
F
OOP
O
OO
O
OH
Cytosine
Deaminase
5-Flurouracil
5-Flurodeoxyuridinemonophosphate