Flashcards in Fitz, Antifungals Deck (52):
Name a polyene antifungal.
What is ergosterol?
Ergosterol is what yeast cell (fungi) membranes are rich in.
MOA of Amphoterecin B.
Binds to ergosterol and forms membrane pores that allow leakage of electrolytes.
Are the membrane pores created by Amphoterecin B hydrophilic or hydrophobic?
hydrophilic membrane pores.
What membrane structural characteristics does Amphoterecin B affect (2)?
1. Disrupts membrane integrity
2. Increases osmotic fragility.
Toxicity of Amphoterecin B:
1. Onset at infusion
2. Later onset
1. Chills, fever, anemia, hypotension
Clearance of Amphoterecin B
Affects of Amphoterecin B on the kidney (2)
Direct DAMAGE TO DISTAL TUBULE membrane (Na/K/Mg wasting) ---> leading to DECREASED GFR.
Amphoterecin B aggravates nephrotoxicity of other drugs in what conditions?
In immunocompromised - transplant, allograft, HIV, people with serious gram negative or MRSA infections.
Name the azoles.
1. Imidazole - ketoconazole
2. Triazole - (1st gen) Fluconazole, Itraconazole; (2nd gen) Voriconazole, Posaconazole
MOA of azoles
Inhibits ergosterol synthesis, the CYP450 enzyme that converts Lanosterol (excess) ---> Ergosterol (deficit)
Name of the CYP450 enzyme that azoles inhibit.
Fluconazole spectrum (and what 2 bugs)
Narrow spectrum - Candida albicans, Cryptococcus
Clearance of Fluconazole v. Itraconazole v. Voriconazole
Fluconazole - RENAL (75%)
Itraconazole - hepatic
Voriconazole - hepatic
Absorption/bioavailability of Fluconazole v. Itraconazole v. Voriconazole
Fluconazole - Good (90%)
Itraconazole - Poor (50%)
Voriconazole - Good (95%)
CSF access of Fluconazole v. Itraconazole v. Voriconazole
Fluconazole - GOOD (so can cover crypto for meningitis)
Itraconazole - POOR solubility
Voriconazole - Good
CYP450 inhibition of Fluconazole v. Itraconazole v. Voriconazole
Fluconazole - Weak
Itraconazole - STRONG drug interactions
Voriconazole - Weak
Half life of Fluconazole v. Itraconazole v. Voriconazole
Fluconazole - ~24 hours
Itraconazole - ~21 hours
Voriconazole - non linear
What does Fluconazole NOT cover?
What azole does cover this?
Voriconazole covers this.
Bugs that Fluconazole covers (2)
Candida albicans, cryptococcus (bc penetrates CSF)
Spectrum and Bugs that Itraconazole covers (5)
-Covers: CANDIDA (Candida albicans, other candida), some aspergillus
-DOC: **Histo, coccidio, blasto**
Bugs that Voriconazole covers (3)
-Candida albicans, other candida
-DOC: **Invasive Asperigillus**
Mechanisms of fungal resistance to azoles.
1. Mutation of lanosterol-14-alpha-demethylase
2. Overexpression of lanosterol-14alpha-demethylase
3. Energy-dependent efflux systems
4. Decreased permeability of fungal membrane (changes in sterol/phospholipid composition)
Name of fungal cell wall synthesis inhibitor class and drugs (3).
Echinocandins ---> Caspofungin, Micafungin, anidulafungin.
MOA of echinocandins
Inhibit cell wall synthesis by inhibiting synthesis of Beta-(1,3)-glucan, leading to osmotic fragility.
Echinocandin method of administration and relative tolerance.
All are infused and are well tolerated (none are oral).
Metabolization of caspofungin
Hepatic (so can give in renal insufficient patients, dialysis, etc).
Use caspofungin/echinocandins for what fungi?
Serious opportunistic infections:
-Invasive candidiasis, candidemia
An AIDS pt has oropharyngeal candiasis and fails fluconazole, amphotericin B, and itraconazole. What antifungal should be administered?
What are echonocandins NOT effective against?
NOT effective against pathogenic fungal organisms
Histoplasmosis is endemic to what region of the US?
DOC for this?
Central, and in locations with humid/warm soild and migratory birds.
**Itraconazole is DOC
Name this 4 opportunistic infections that are therapeutic indications for Triazoles
Name this 4 pathogenic infections that are therapeutic indications for Triazoles
Oropharyngeal Candidasis (thrush), or immunocompromised, use what?
Most fatal mycoses in Non-HIV patients.
Admin method of Ketoconazole
Dissolution of what two antifungals require gastric acidity?
-Pill-form of ketoconazole
What is a ketoconazole drug interaction?
Inhibits CYP450 drug interactions
A person starts taking an antifungal and comes back with decreased libido and gynecomastia. What drug was given?
Ketoconazole - Inhibits adrenal and gonadal steroid synthesis
Do imidazoles or triazoles disrupt testosterone synthesis?
triazoles have no endocrine abnormalities.
What two triazoles are strong inhibitors of hepatic CYP450 and enhance renal toxicity?
Voriconazole and Itraconazole
Vision disturbance, think what triazole.
When should triazoles be avoided and what damage can they cause?
Avoid in pregnancy.
All can damage liver.
DOC for mucormycosis
DOC for cryptococcal meningitis
Amphotericin B + 5-Fluorocytosine antimetabolite
5-FdUMP inhibits what
5-FdUMP inhibits Thymidylate Synthase = inhibition of DNA synthesis
5-FUTP inhibits what
5-FUTP inhibits protein synthesis
5-FC extracellular --(membrane bound Cytosine Permease)--> 5-FC intracellular --(cytosine deaminase)--> 5-FU ---> 5-FUMP ---> 5-FdUMP or 5-FUTP
Mechanisms of resistance of 5-FC
1. Intrinsic - mutation in Cytosine Permease
2. Acquired Resistance - mutation in Cytosine Deaminase
How do AMP-B and 5-FC work together?
Amp-B creates ergosterol pores so that more 5-FC can get in.
DOC for invasive fungal infection, unresponsive to other therapy