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51 Cards in this Set
- Front
- Back
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Opportunistic fungal infections are more common in:
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Hospitals
Patients with compromised immune system (AIDS, chemotherapy, organ transplant) |
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What are common opportunistic fungi?
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Candida (yeast)
Aspergillus (mold) Pneumocystis carnii Cryptococcus (hidden seeds) Mucor (mold) |
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Name the 3 biochemical targets for antifungal chemistry
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1. Disturbance of fungal cell membrane
2. Inhibition of fungal cell wall synthesis 3. Inhibition of fungal DNA synthesis |
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What are the 2 ways that antifungals can disturb the fungal cell membranes? Which antifungals do this?
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Suppression of ergosterol synthesis (azoles, allyl amines/naf-fines)
Direct binding and permeation (polyenes) |
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Name the 4 types of agents used to treat invasive fungal infections
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Azoles
Polyenes Echinocandins Flucytosine |
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What are the 3 drugs in the Echinocandin category?
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Caspofungin
Micafungin Anidulafungin |
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The molecular target of azole compounds is...
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14α-demethylase (member of CYP450)
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What does 14α-demethylase normally do?
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It demethylates lanosterol, an intermediate in ergosterol synthesis.
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The first orally active and most extensively used antifungal agent is:
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Ketoconazole! :D
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An important structural feature of azoles are:
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Imidazole ring
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What do fluconazole, voriconazole, itraconazole and posaconazole have in common?
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They are triazole antifungal agents
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Which agents are triazole antifungals?
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Fluconazole
Voriconazole Itraconazole Posaconazole |
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Which triazole antifungal should be reserved for serious fungal infections?
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Posaconazole
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What is the mechanism of action of azoles antifungals?
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Azole compounds bind to heme ion on 14α-demethylase via imidazole or triazole ring.
Inhibits ergosterol synthesis--> accumulation of abnormal intermediate steroid on the fungal membrane. The fungal membrane becomes leaky, leading to fungal cell death. |
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True or false. Nystatin and Natamycin can be administered systemically
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FALSE. Nystatin and Natamycin are too toxic to be administered systemically
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True or false. Amphotericin B can be administered systemically
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TRUE. Amphotericin B is the only polyene that can be administered systemically.
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What is the drug of choice for life threatening fungal infections?
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Amphotericin B
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What are the limitations of Amphotericin B?
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Serious toxicity- renal toxicity, fever, shaking chills, hypotension
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Which polyenes can be applied topically?
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Nystatin
Natamycin |
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Which polyene is used for fungal infections of the eye?
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Natamycin
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Fungizone
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Amphotericin B deoxycholate (AmBD)
Deoxycholate is a detergent |
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Abelcet
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Amphotericin B lipid complex (ABLC)
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Amphotec
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Amphotericin B cholesteryl sulfate complex
Amphotericin B colloidal dispersion (ABCD) |
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AmBisome
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Liposomal amphotericin B (L-AmB)
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What is unique about the structure of AmBisome?
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Amphotericin B is incoproated in the lipid bilayer of liposomes (lipid vesicles with an aqueous interior)
Liposomes are 45-90nm diameter. Saturated lipids with high transition temperature. |
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What is the benefit of the liposomal structure of AmBisome?
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Liposomal complex results in slower release of Amphotericin B into the blood stream. This allows Amphotericin B to selectively disrupt fungal cell membranes
They can also help with more distribution to the site of the infection. |
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What is the problem with traditional Amphotericin B?
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Traditional Amphotericin B dissolves and results in a spike in the blood stream. So it disurupts both fungal AND mammalian cell membranes.
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Compare Amphotericin B and AmBisome
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Ambisome has a smaller percentage of breakthrough fungal infection, death due to fungal infection, fever/chills, and nephrotoxicity compared to Amphotericin B.
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Describe the structure of Abelcet (ABLC)
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Amphotericin B complexed with 2 phospholipids in a 1:1 drug to lipid molar ratio.
The two phospholipids, L-a-dimyristoylphosphatidylcholine (DMPC, C14) and L-a-dimyristoylphosphatidylglycerol (DMPG, C14), are present in a 7:3 molar ratio. |
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How many carbons are present in Abelcet?
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14
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What is the relationship between length of the lipid chain in AmBisomes and their transition temperature?
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The longer the chain, the higher the transition temperature
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Does AmBisome or Abelcet have the higher transition temperature?
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AmBisome
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Describe the chemical composition of Amphotec
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1:1 molar ratio complex of Amphotericin B and cholesteryl sulfate
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Explain why the Vd of AmBisome is small compred to other Amphotericin B drugs
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After administration, the drug is kept in the liposome. Liposomes are too large to distribute freely into local tissues so more drug is kept in the central compartment for a long time
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What is the significance of the lipid formulations of Amphotericin B and their dose?
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All lipid formulations of amphotericin B can have a dosage as high as 5mg/kg. You cannot have a dose this high for the traditional amphotericin B.
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Which amphotericin B formulation had the highest Cmax, AUC, plasma concentration and CSF concentration?
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AmBisome
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Compare toxicity of AmBisome to the other lipid compositions of amphotericin B.
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AmBisome carries less toxicity and nephrotoxicity compared to Abelcet.
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What is the mechanism of action of Echinocandins?
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Echinocandins inhibit β-(1,3)-D-glucan synthase
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What is the basis of selective toxicity for echinocandins?
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Cell wall is critical for the integrity of fungal cells but not present in mammalian cells.
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Describe the four layers comprising the fungal cell wall
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1. Cellular membrane composed of ergosterol and phopholipids
2. High molecular weight, cell surface proteins (Invertase, Acid phosphatase) 3. Polysccharide layer 4. Strongly associated external protein layer |
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What is the importance of the fungal polysaccharide layer?
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Essential for withstanding osmotic pressure
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What is the importance of the external protein layer?
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Fibrillar
Essential for cell adhesion |
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What is the chemical composition of the polysaccharide layer of the fungal cell wall?
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Glucans: β-(1,3)-D-glucan, β-(1,4)-D-glucan, β-(1,6)-D-glucan, α glucans
Chitin Mannan or galactomannan Glycoproteins |
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Which glucans in the polysaccharide layer can cross link?
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β-(1,3)-D-glucan
β-(1,6)-D-glucan |
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What is the mechanism of resistance against echinocandins?
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Mutations of Fsk1 gene which lead to decreased binding of β-(1,3)-D-glucan synthase.
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What are the two chemical moieties of echinocandins?
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Cyclic hexapeptide moiety with unusual amino acid residues (charged in capsofungin and micafungin)
Lipophilic chain, which is thought to interact with the lipid bilayers |
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Which echinocandins are water soluble?
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Casofungin
Micafungin |
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Which echinocandins are not water soluble?
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Anidulafungin
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How are echinocandins administered?
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Slow IV infusion
(Poor oral bioavailability) |
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What adverse reaction is caused by echinocandins?
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Immune shock (histamine release, bronchiolar spasm) if the infusion is too fast
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How are echinocandins metabolized?
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Degraded by the liver by hydrolysis and N-acetylation
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