Unit 09: antifungals Flashcards
illnesses caused by fungi
- wide variety including asehtma or allergies, skin issues, lung infections, blood infections and meningitis
what are fungi and thier forms
considered primitive plants and can exist in various forms: unicellular yeast like (candida), filamentous mold (aspergillus) and some are yeast like inside body but filamentous outside (Blastomyces)
*eukaryotic so harder to attack without attacking the host
what is the other name for fungal infections?
mycosis
what are the 5 main antifungal drug classes
Polyenes, azoles, pyrimidines, echinocandins and terbinafine
what are examples polyenes
amphotericin B, nystatin and natamycin
common fungicidal agents but they have high systemic toxicity.
what are examples fo azoles
itraconazole and voriconazole
- very low toxicity and considered to have fungistatic effects
examples of pyrimidines
- flucytosine
- agents that can penetrate BBB
ex of echinocandin
capsofungin
- newer class of antifungal which appear to ahve low toxicity
what is used to treat dermatophytosis
*fungal infection in the skin
- treat with terbinafine
primary molecular targets for antifungal therapy
- enzymes and other mol invovled in fungal DNA synthesis, mitosis, plasma membrane synthesis adn cell wal synthesis
- PM of fungi is unique in that it contains ergosterol not cholesterol which makes it a target for amny antifungals
what classes of antifungals inhibit ergosterol synthesis
allylamines, benxylamines, imidazoles, and triazoles
what antifungal targets the cell wall? what targets the PM?
echinocandins targets cell wall
Polyenes parget the Plasma membrane
what antifungal targets DNA synthesis
flucytosine
what antifungal targets mitotic spindle?
Griseofulvin
what is amphotericin B
a polyene antifungal agent that attacks by binding to ergosterol and dsitrupting fungal membrane stability
- when it binds it produces channels or pores that alter fungal membrane permeability and allow for leakage of essential cellular contents ultimately leading to cell death
what are soem drawbacks to amphotericin B and adverse effects
resistance is becoming more common and drug also bidns to cholesterol fairly easily so can lead to toxicity
adverse effects:
- Nephrotoxicity: patients see urine changes (protien, blood or casts) before increased levels of urea and nitrogen would be noted in blood
- also fever, vomiting, nausea, phlebitis (inflammation of veins)
- IV administration may cause thrombosis therefore infusion must be slow (over 4-6 hours)
- administration of fluids containing NaCl prior to treatment may lessen nephrotoxicity
*lipid complex formualtions are safer and preferred to reduce kdiney damage
when is amphotericin B used?
mainly in patients with life treatening systemic mycoses (esp if immunocompromised) bc its fungicidal
*For immunocompetent patients, many practitioners prefer the safer azoles (such as itraconazole) even though most azoles are fungistatic
spectrum of amphotericin B
- broad spec of activity (broader than azoles) but inefective against dermatophytes (like ringworm)
- often given once prior to longer follow up therapy with azoles but not usually combined bc azoles may reduce ergosterol bidnign sites for amphotericin B
why use lipid formulations of amphotericin B? what are the ones available?
- Abelcet® (lipid complex), Amphotec® (colloidal) and AmBisome® (liposomal)
- muhc less toxic and can be infused at higher dosages over a period of 1-2 hours making them more effective
- usually given 3x a week or once prioir to azole therapy
- must have blood urea and N levels monitored twice a week
*possible that nephrotoxicity may not become evident for 3-4 weeks after treatment with the drug has stopped.
pharmacokinetics of amphotericin B
- distributed in extracellular space everywhere except the CNS
- lipid complex Abelcet concetrates in lungs and the reticuloendothelial system - significant therapeutic advantage
- half life is more than 100 hours, drug cont to be excreted weeks after disc of therapy
- metabolized in liver in the bile and metabolites and active drug will be excreted in the urine.
what are azoles
ex: imidazoles and triazoles
newer class of drugs compared to polyenes
broad spectrum of activity, are safer and have good oral bioavailability
downside of azoles
teratogenic: interfere with embryonic retinoic acid homeostasis and should therefore be avoided in pregnant individuals.
imidazole vs trizoles
older imidazoles such as ketoconazole are less effective and more toxic than newer triazoles such as itraconazole
*imidazoles have more of an effect on mammalian sterol synthesis than triazoles
- imidazoles have more endocrine adverse effects
ex of imidazoles
Ketoconazole (systemic)
Clotrimazole, miconazole (topical)
ex of triazoels
Fluconazole
Itraconazole (oral)
Posaconazole
Voriconazole
*top to bottom is inc spectrum
How do Triazoles work?
- inhibit fungal P450 enzymes that are involved in ergosterol formation, specifically sterol-14α-demethylases
*take with caution because also inhibit mammalian hepatic P450 enzymes
what is the major draw back of triazoles?
- usually a fungistatic
- at high label tose itraconazole may have fungicidal activity as well though
- also resistance is becoming more common especially with itraconazole and fluconazole (narrowest spectrum of activtiy)
general distribution of triazoles and the exception
most triazoles distrubte well in body except to CNS
*Fluconazole is exception bc it distributes everywhere inclusing the CNS
- triazoles concnetrate in the skin, half life is approx two days and drug is eliminated mainly by hepatic metabolism
*exception is fluconazole which is eliminated in urine
adverse effects of triazoles
- not very common bc triazoles interfere with host hepatic enzymes much less than imidazoles
- hepatic and GI effects are common with ketoconzaole
- may also cause liver problems at higher doses and contraindicted in pregnancy due to at least two diff teratogenic mechanisms
what it Itraconzole
- oral administration
- treat non life treatening fungal infections, fairly good spec of activity
- not effective against aspergillus or candida as the polyenes or the newer triazole coriconazole
- sometimes itraconzole can be used in palce of amphotericin B to treat life threatening infections
what is fluconazole
- a triazole
- unlike other azoles it distributes will to CNS
- oral bioavailability of 100% and can be given via IV
- half lifke is 20-40 hours so a singel roal dose may be effective in some cases
- may be as effective as emphotericin B for cryptococcal meningitis and its effective against dermatophytes
what is voriconazole
- type of triazole
- derivative of fluconazole
- also has excellent bioavilaablity and distirbution including into the CSF
- broadest spectrum of activity of all triazoles
what is Posaconaozle
type of triazole
- its a derivative or itraconazole
- oral bioavailability is good but not as good as fluconazole or voriconazole
- in terms of spec of activity it is as broad as or potentialy even better than voriconazole
what is Flucytosine and how deos it work
- fluorinated pyrimidine that is susceptible to fungi (mainly Cadida and cryptococcosis)
- acts by metabolizing 5-fluorouracil which is incorperated into mRNA and inhibits protein synthesis
- 5-FU is futher metabolized to compounds that inhibits DNA synthesis
*Note that mammalian cells are not affected as they do not convert flucytosine to 5-FU.
when would you prescribe flucytosine
- bc it readily enters the CNS it is mainly used in fungal cryptococcal meningitis in combination with toehr drugs
- Fungal meningitis often requires aggressive therapy and may be fatal despite treatment
drawbacks of flucytosine
- narrow spectrum on its own and resistance is common, so never prescribe alone
*hapatotoxicity and bone marrow suppression may occur following use
what is the MOA of flucytosine?
- enters the fingal cell ia a transmembrae cytosine permease
- inside the cell cytsine deaminase converts flucytosine to 5-fluorouracil which is subsequently converted to 5- 5-fluorodeoxyuridylic acid monophosphate (5-FdUMP)
- 5-FdUMP inhibts thymidylate synthase and therby blocks the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP)
- in absense of dTMP, DNA synthesis is inhibited
what are examples of Echinocandins
caspofungin, micafungin and anidulafungin,
MOA of echinocandins
unique mechanism of action where they inhibit beta-(1,3)-D-glucan synthase - an enzyme necessary for the synthesis of an essential component of the cell wall of several fungi.
fingistatic vs fungicidal activity of echinocandins?
fungistatic against aspergillus species
fungicidal against msot Candida species (including strains taht are fluconazole resistant)
when woudl you prescribe Echinocandins?
- to treat esophageal candidiasis, candidemia and invasive candidiasis
* caspofungin has demonstrated efficacy as salvage therapy for the treatment of invasive aspergillosis and it is the only echinocandin approved for use in pediatric patients.
resistnace to echinocandins and adv effects
- resistance is rare
- all agents well tolerated with simialr adverse efect profiles (fever, rash and nausea) and few drug-drug interactions
*expensive, but may work synergistically with polyenes or azoles
what is Terbinafine
inhibits ergosterol synthesis in virtually all dermatophytes.
Dermatophytes, such as ringworm, causes dermatophytosis, which is a clinical condition resulting from a fungal infection that infects the skin, hair or nails
distribution of terbinafine
distributes to skin, nails, fat and milk
- usually not recommended for preg patients
when u give terbinafine and details on the therapy
more effective than itraconazole
given orally for serious infections
-half-life is extremely long, about two weeks.
Therapy usually lasts for approximately three months and much longer for nail infections (onychomycosis).
The main adverse effects include gastrointestinal upset, headache and rash.
