Burkin: Fungal Pharmacology Flashcards
Compare bacteria and fungi in terms of :
Cell size
Ribosomes
Cell wall
Membrane
bacteria are much smaller;
bacteria use 70S vs 80s ribosomes in fungi;
cell wall made of peptidoglycan in bacteria and chitin in fungi;
membrane has no sterols in bacteria and ergosterol in fungi
What 4 drug types are used for systemic fungal infections?
polyene antibiotics
imidazole and triazole drugs
flucytosine
pentamidine
What antifungal drugs are used for superficial infections?
polyenes
azoles
griseofulvin
naftifine
How do polyene antibiotics work?
they are large lipophilic, water insoluble molecules and they dissolve into the cell membranes of fungi, bind to ergosterol in the membrane and increase the permeability to ions and metabolites
What is the selectivity like for polyenes?
selectivity is poor, because polyenes bind to sterols in the membrane and human cell membranes also contain sterols
What are two polyenes that are usually applied topically?
Nystatin
candicidin
What is one polyene that is the drug of choice in most systemic fungal infections, including systemic candidiasis?
Amphotericin B
What is candicin used for?
used topically for vaginal candidiasis
What are the adverse reactions caused by polyenes?
many ADRs - these drugs are not very selective, so they are quite toxic
**watch out for fever and nephrotoxicity
What are the two general categories of antifungal azole drugs?
imidazoles (2 N in a ring)
triazoles (3 N in a ring)
What is its mechanism of action of the imidazoles and triazoles?
imidazole; blocks ergosterol synthesis by inhibiting fungal 14-alpha demethylase, a cytoP450
Which class of azoles does Ketoconozole belong to? What is it used for?
it is an imidazole; it is used as an alternative (second line due to toxic effects) to amphotericin B for treating systemic fungal infections
What is the main toxicity effect you want to look out for with ketoconozole? When should you discontinue ketoconazole?
hepatic toxicity
gynecomastia (inhibits cytoP450s involved in human steroid synthesis;
DISCONTINUE IF HEPATITIS OCCURS
Besides ketoconazole, what are two other imidazole antifungals? What are they used for?
miconazole: treatment of dermatophyte infection and vaginal candidiasis
clotrimazole: topical treatment of cutaneous and vaginal infections
Imidazole antifungal used for dermatophyte infection and vaginal candidiasis
miconazole
Imidazole antifungal used for topical treatment of cutaneous and vaginal infections
clotrimazole
What are 3 triazole antifungals?
itraconazole
fluconazole
variconazole
Which triazole antifungal is used for several systemic infections, because it has a wider spectrum of activity than ketoconazole and fewer adverse effects?
itraconazole
What is fluconazole used for?
cryptococcal meningitis in patients with HIV
Candida in immune compromised patients
This is the most frequently prescribed antifungal drug; great for cryptococcal meningitis and candida
fluconazole
This is now the drug of choice for several systemic mycoses
itraconazole
**has replaced ketoconazole for treatment of systemic mycoses
Name two allylamines
Naftifine *topical
Terbinafine *oral
What is the mechanism of action for allylamines?
they inhibit squalene epoxidase –> buildup of intracellular squalene concentration –> decreases ergosterol synthesis
What are the allylamines used for clinically (2 things)
dermatophytes
Candida
What are the steps going from squalene to ergosterol?
squalene –> squalene epoxide via squalene epoxidase
squalene epoxide –>lanosterol
lanosterol –> ergosterol via 14alpha-demethylase
Which step in ergosterol synthesis do Naftifine and Terbinafine block?
squalene epoxidase which takes squalene to squalene epoxide
Which step in ergosterol synthesis do the azoles block?
lanosterol –> ergosterol via cytoP450 dependent 14alpha-demethylase
How is flucytosine converted to its active form? What is its mechanism of action?
converted to 5-flurouracil by fungal cytosine deaminase; works by blocking DNA and RNA synthesis by blocking thmidylate synthetase
What is flucytosine used for?
in combination with amphotericin B to treat systemic crytococcus and candida infections
What are some adverse reactions when using flucytosine?
bone marrow depression
GI distress
reversible hepatotoxicity
How does pentamidine work?
binds to kinetoplast DNA and inhibits mitochondrial DNA synthesis
What is pentamidine used for?
Pneumocystis jiroveci
Also effective against African trypanosomes
What is the method of action of griseofulvin?
it binds to tubulin in cells, which is a protein that makes up microtubules - it prevents the proper separation of chromosomes during mitosis and interferes with transport functions of microtubules
Where is griseofulvin found in high concentrations?
keratin in skin and hair
What is griseofulvin used for clinically?
dermatophyes (fungus that causes skin infection)
*Trichophyton, Epidermophyton and Microsporum
When is griseofulvin best absorbed?
when taken with a fatty meal
