Flashcards in Antifungal drugs Deck (50)
Amphotericin B, a polyenes used to treat systemic antifungal infections, what makes it so good and what makes it so bad?
good: broadest spectrum
bad: significant adverse side effects
(there are newer liposomal formulations associated with increased efficacy and decreased toxicity)
How is amphotericin given, what is its mechanism of action?
1. binds to ergosterol in fungal membrane
2. forms pore in the membrane thereby increasing membrane permeability
3. efflux of essential molecules
4. fungal death
-binds only weakly to cholesterol
What is amphotericin B not active against?
1. Candida Lusitaniae
2. Pseudallescheria boydii (scedosporium apiospermum)
When is amphotericin used?
initial induction therapy (usually 4 weeks) to reduce fungal burden, then replaced by newer less toxic AZOLE drugs for consolidation therapy and prevention of relapse
What is the ONLY antifungal agent that is approved in pregnant/ breast feeding women?
What is amphotericin the treatment of choice for?
What are the adverse infusion related effects for amphotericin a drug with a low therapeutic index ?
1. infusion related
-fever, chills, muscle spasms, vomiting, headache and hypotension
a. slow rate/decrease dose
b.preemptive meds like antipyretic,antihistamine, corticosteroids
What are the cumulative toxicities of amphotericin B?
a. reversible-decreased renal perfusion via vasoconstriction
-reduce by using saline drip (Na loading)
b. non reversible
-renal tubular injury(prolonged administration)
-tubular acidosis and severe K+ and Mg2+ wasting
-more common in presence of diuretics or other nephrotoxic meds eg. aminoglycosides/cyclosporine
2. hepatotoxicity (occasional)
-reversible suppression of erythrocyte production due to decreased EPO
What are the bad parts of flucytosine and the good part?
1. narrow spectrum of activity
2. use is restricted by high incidence of resistance
-mutations in cytosine permease, cytosine deaminase, uracil phosphoribosyl transferase or increase in cytosine synthesis
good penetration into the CSF
-used for cryptococcal meningitis
Is flucytosine used alone?
no typically in combination with other antifungal drugs
-especially ampho B and an azole
-ampho enhances flucytosine permeability
How is flucytosine eliminated?
renally-dosage adjustment required in presence of renal insufficiency
What is the mechanism of action of flucytosine?
1. taken up via cytosine permease
2. fungal specific cytosine deaminase -->5 fluorouracil
2. inhibits both DNA(thymidylate synthase) and RNA synthesis
What does flucytosine+amphotericin B treat?
cryptococcosis and candidiasis
-cryptococcal meningitis (good CSF penetration of flucytosine and ampho b enhances fungal uptake of flucytosine)
What does flucytosine + itraconazole treat?
What are the adverse effects of flucytosine?
1. endogenous gut microflora express cytosine deaminase -->5 fluorouracil (antimetabolite)-->toxicity
-GI: nausea, vomiting diarrhea
-Bone marrow toxicity: anemia, leukopenia, thrombocytopenia
What is the prototype imidazole?
What is the order of spectrum of activity for the triazoles?
What is the mechanism of action of azoles?
Azoles are fungistatic/fungicidal
1. Inhibit 14 alpha demethylase (CYP45) involved in biosynthesis of ergosterol from lanosterol
-impairs membrane function
-increases membrane permeability
-decreases activity of membrane associated proteins
What are the common adverse side effects of all azoles?
1. GI distress
2. Hepatotoxicity-requires hepatic enzyme monitoring
3. fetal abnormalities
When should itraconazole and voriconazole never be given to a patient?
when the patient is taking statins due to increased risk of developing rhabdomyolysis
What azoles have good CNS penetration?
fluconazole and voriconazole
What azole needs real adjustment?
What limits ketoconazole use?
-oral ketoconazole requires acidic environment for absorption
-poor penetration into CSF and urine
-many adverse effects due to inhibition of CYP450 enzymes involved in adrenal and gonadal steroid synthesis
-->decreased cortisol and decreased testosterone
--->gynecomastia, libido, impotence, menstrual irregularities, hypotension and fatigue
-many drug interactions of CYP450 3A4
-rarely used now, largely replaced by itraconazole
-still used topically to treat dermatophyte infections
What is the spectrum of activity fluconazole?
Narrowest spectrum of activity of all azole drugs but
-good oral bioavailability and EXCELLENT penetration into the CSF
-fewest drug interactions of all azoles
Does fluconazole have many adverse effects?
no only minor effects: nausea, headache, skin rash and GI, and alopecia (reversible, long/high dose)
How is fluconazole eliminated?
80% of drug eliminated unchanged in the urine
-useful in treatment of fungal BLADDER infections
What does fluconazole used to treat?
-poor activity toward C. glabrata and no activity against C. krusei
2. TREATMENT OF CHOICE
for cryptococcal meningitis
-used as consolidation/maintenance therapy with ampho b/flucytosine
3. good activity against coccidioides
4. variable activity against endemic dimorphic fungi
-less active than itraconazole against histoplasmosis, balstoplsmisis, sporotrichosis
-only used if itraconazole not well tolerated
What is fluconazole the therapy of choice for?
1. Cryptococcal meningitis
2. coccidioidal meningitis
What should itraconazole not be used for?