Anti-fungal drugs Flashcards
Fungal cell structure and targets
-
fungal cell wall
- most medically relevant fungi have a cell wall composed of proteins and carbs including mannoproteins, chitin, glucan polymers
2. cell membrane
- major sterol for mamals cells: cholesterol
- major sterol for fungal cells: ergosterol
3. metabolism
- diferences in nucleotise metabolism from mammalian cells
polyene antifungal agents
structure:
mech:
prep:
Amphotericin B
Nystatin (too neprotoxic for systemic use, often used topically)
structure: multiple conjugated double bonds, internal ester, glcoside side chain
mech: moles form channel allowing loss of intracellular cations
original prep of amphotericin: solubilized with deoxycholate as micellar suspension
Amphotericin B
spectrum
extremely broad
- active against most medically related fungi
Antifungal triazoles
absorption:
distribution:
mech:
drug interactions:
apsorption:
- excellent for fluconazole
- poor for itraconazole tablets (esp in high pH)
- antacids decreased absorption of itraconazole
distribution: variable
- excellent CSF penetration by fluconazole and voriconazole
- poor CSF penetration by posaconazole and itraconazole
MEch of action:
- inhibition or ergosterol synthesis by interfering with Iansterol 14alpha demethylase, a funglal CYP450 molecule
Interfere with our CYP450 metabolism of many other drugs:
- durg-drug interations much be careful
- ex. inhibit metabolism of warfarin, increasing anticoagulant effect
- Rifampin enhances metabolism of azoles
terbinafine
inhibits squalene epoxidase step in erosterol biosyn
oral and topical formulations
indicated for onychomycosis, tinea
Gi upset, hepatotoxicity
Griseofulvin
inferferes with microtubule assembly
well tolerated, inexpensive, but useful only for tx of skin infections
rare, peds cases
being replaced by itraconazole and terbinafine for many uses
classes of anti-fungal agents
- disruption of fungal cell wall
- disruption of fungal cell membrane
- antimetabolites
- microtubule assembly inhibitor
1. disruption of fungal cell wall
- Echinocandins: caspofungin, anidulafungin, micafungin
2. diruption of fungal cell membrane
- allylamine: terbinafine
- azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole
- polyenes: ampho B, including lipid formulations
3. antimetabolite
-
pryimidine analogue: 5-flucytosine (5-FC)
4. microtubule assembly inhibitor - griseofulvin
Amphotericin B
admin:
major toxicities:
administration:
- IV only for systemic use
- topical for sinus use
- unilaminar liposomes with Ampho B
- Major toxicities
- infusion- related rxns (75%): fever, chills, myalgias, nausea, vomiting, headache
- can be minimized by slow infusion, pretreatment with acetaminophen, hydrocortisone
nephrotoxicity
- tubular injury
- azotemia (increased blood urea nitrogen, creatine), hypomagnesemia and hypokelemia
- nephrogenic diabetes insipidus
- can be minimized by “saline loading”, avoid other nephrotoxic agents
- patient with worst infection- use AMpho B
Azoles
spectrum:
ketaconazole- modestly effective- candida, aspergillus, not well absorbes, multiple doses needed
fluconazole- candida, cocciodes, cryptococcal pneumonia
itraconazole- expanded to aspergillus, durg of choise for histoplasmosis
voriconazole- expnaded and enhanced pharmacokinetics for molds, aspergillus
posaconazole- same as vori + zygomycosis
anti fungal
spectrum slide, admin route
fluconazole:
itraconazole and voriconazole:
posaconazole:
fluconazole
- active against most cryptococcus, candida sps (C.krusei resistant)
- aspergillus sps are resistant
- IV and PO
itraconazole and voriconazole
- active against most candida sps
- active against more aspergillus sps
- voriconazole is tx of choice for most invasive aspergillus
- itra PO only, vori IV and PO
posaconazole
- active against most candida, aspergillus, many molds, zygomycosis
- PO only
Echinocandins
- caspofungin, anidulafungin, micafungin
Mech:
toxicities:
admin:
spectrum:
mech:
-inhibit beta glucan synthetase activity, interfering with synthesis of cell wall component
toxicitites:
- well tolerated compared to polyenes
- fewer toxicities and drug interactions that triazoles, but casofungin alters metabolism of tacrolimus
admin:
IV only
Relative clinical efficacy compared to triazoles and plyenes not certain
**spectrum: **
FDA approved for invasive infections due to aspergillus and candida
5-flucytosine
mech:
toxicities:
admin:
mech:
- taken up by fungal cells, converted in cytoplasm by cytosine deaminase to 5-fluoruracil, phophorylated, then inhibiting DNA, RNA synthesis
Toxicities:
- Gi intolerance, bone marrow suppression, rashe,s eosinophilia
admin:
PO only
Used synergistically with AmphoB for certain candida infections, cryptococcal meningitis
Topical antifungals
polyenes: amphotericin, nystatin
azoles: ketaconazole, butoconazole, clotrimazole, econazole, miconazole
allylamine: terbinafine, naftifine
antimetabolites: ciclopirox, tolnafte…
Dermatophyte (tinea) infections
most common
tinea coporis, crusis, pedis- topical antifungals
- clotrimazole, econazole
- avoid use of product with corticosteroids
tinea capitis (hair follicles)- systemic therpy needed
- terbinafine, itraconazole, griseofulvin, fluconazole
onychomycosis (nail infections due to fungi), systemic therapy needed
- terbinafine, itraconazole, grisefulvin, fluconazole
