Anti-fungal drugs Flashcards
What drug binds to membrane ergosterol?
amphotericin B
How is amphotericin B administered?
topical or IV (not oral)
Which class of drug inhibits lanosterol demethylase? Results?
- azole drugs
- inhibits ergosterol synthesis
Which azole drug subtype inhibits CYP450 proteins?
triazoles
Which drug directly disrupts the cell wall? When is it used?
- caspofungin
- IV for azole-resistant infections
What drugs inhibit enoyl reductase? What is disrupted?
- Isoniazid, ethionamide
- mycolic acid synthesis
Two AE’s associated with isoniazid?
- neuritis
- hepatotoxicity
What enzyme is inhibited by rifampin?
DNA-dependent RNA polymerase
What is induced by rifampin?
CYP450
Difference between effectiveness of fluconazole and itraconazole?
similar, but flu is less effective in the lungs
How are blast patients typically treated?
- itra/keto
- ampho
Benefits of triazoles over imidazoles?
- tri’s last longer and have fewer cross-reactions
How do azole drugs work?
- inhibit lanosterol demethylase, a CYP450 enzyme that is important in membrane structure and O2 transport in fungi
What effects can azole drugs have in humans?
- inhibition of human CYP450 lanosterol demethylase
- inhibit human sterol synthesis and can alter metabolism of other drugs
What is a common chemotherapeutic agent whose effectiveness is decreased by azole drugs?
- cyclophosphamide
- activated by CYP450
What class of anti-fungals are teratogens?
azole drugs - disrupts hormonal synthesis and inhibits aromatase
Differences between ketoconazole and itraconazole?
- older imidazole with lots of drug interactions
- itra is newer triazole with less severe interactions
What 6 drugs have significant interactions with azoles?
- warfarin, cyclosporine, phenytoin
- lovastatin, oral hypoglycemics, protease inhibitors
What drug binds to ergosterol in the fungal cell membrane and disrupts the membrane?
amphotericin B
What anti-fungal is pretty useful against a BROAD spectrum of fungi?
amphotericin B AND it crosses the BBB
What is the principal dose-limiting toxicity with amphotericin B?
renal dysfunction - also hypotension, hypokalemia, reversible normocytic anemia, thrombophlebitis
Pharmacodynamics of azoles?
- Itra and keto are highly protein-bound in the bloodstream
- Flu crosses BBB readily
How is cocci treated? What other types of drugs should be avoided with this treatment?
- amphotericin B
- anti-virals also cause renal toxicity
What is the new SOC for invasive aspergillosis?
voriconazole (traditionally amphotericin)
What class of drug is caspofungin? How does it work?
- echinocandin
- non-competitively inhibits synthesis of fungal cell wall by being a lipopeptide that causes fungal cells to lyse
What two diseases is caspofungin approved for?
- invasive aspergillosis
- esophageal candidosis
- WHEN ampho/fluconazole have failed
How is caspofungin administered and why?
- IV
- not absorbed by GI tract
Why must TB treatments last 6 months?
- granulomatous immune response
- organisms have thick waxy coats and can form resistant little masses in the lungs
When is ethambutol included in a TB regimen?
when isoniazide resistance exceeds 4%
Standard 4 drug TB regimen?
- PIER
- pyrazinamide, isoniazide, ethambutol, rifampin
MOA of isoniazid?
- inhibits enoyl reductase blocking my colic acid synthesis
What enzyme activates isoniazid?
KatG - catalase/peroxidase
What drug may inhibit uptake of isoniazid?
Al-containing antacids
What enzyme metabolizes isoniazid? Who is this a problem in?
- liver N-acetyl transferase
- 50% of American Caucasians and 15% of Asians are slow acetylators
How is neuritis associated with isoniazid administration treated?
- pyridoxine
- isoniazid looks like Vit B6 so large doses of B6 can displace it from non-target sites
3 TB drugs associated with hepatotoxicity?
- isoniazid
- rifampin
- pyrazinamide (hepatitis)
What 4 drugs are affected by induction of CYP450 by rifampin?
- prednisone, digitoxin, quinidine, propanalol
What are the anti-TB effects of pyrazinamide?
- unknown MOA
- inhibits my colic acid biosynthesis
What are the anti-TB effects of ethambutol?
- unknown MOA
- interferes with metabolism, replication
AE associated with ethambutol?
- optic neuritis = blurring, red-green perception loss
- reversible
What TB drugs are associated with high rates of resistance?
isoniazid and rifampin
What three drugs are added in second-line anti-TB therapy?
- streptomycin
- ethionamide
- p-aminosalicylate
How does p-aminosalicylic acid work in an anti-TB regimen?
- competitive inhibitor of PABA (folate synthesis)
- specific for tubercle bacilli but has severe GI and hypersensitivity effects
How does ethionamide work?
- pro-drug that inhibits the same step as isoniazid (enoyl reductase) but by a different mechanism
- inhibition of my colic acid synthesis
AE’s associated with ethionamide?
GI effects (vs. neuritis, hepatotoxicity, rash, fever, hypersensitivity)
