Chapter 3 Drug Structures Flashcards
(27 cards)
Amphoteracin B antifungal
Less toxic than nystatin
ADR: HSR, anemias, nephrotoxicity, bone marrow suppression, injection site reaction
Use: all, mainly aspergillus and cryptococcus
use in combo with antihistamine or corticosteroid to treat injection site pain prophylatically
the polyalkene structure allows the drug to partition into the fungal membrane and disrupt bonding interaction so that it cannot function. Transport ions also become dysfunctional. It does not affect biosynthesis of cell memebrane.
Nystatin antifungal
too toxic for systemic use
molecules are too polar and large, so even if you accidentally swallowed soome nystatin it could not be absorbed
Use: candida albicans
It does not affect biosynthesis of cell memebrane. It disrupts cell membrane
liposomal amphotericin B
tends to produce least infusion toxicity, electrolyte imbalances, nephrotoxicity, and anemia
very costly
5-Flucytosine
Use: candida and cryptococcus
oral administration
rapid aquisition of resistance when drug is used alone
ADR: GI upset, bone marrow suppression, hepatotoxic
Be cautious with renally impaired pt
Mech: The triphosphate form of 5-FC inhibits RNA synthesis. The monophosphate form inhibits dTMP formation and thus DNA biosynthesis.
blocks fungal protein synthesis via incorporation of abnormal RNA and it blocks DNA by inhibiting thymidylate synthetase(cannot make T)
Butoconazole
imidazole antifungal
imidazole general structure: multi-halogenated aromatic ring, imidazole ring, and a second halogenated aromatic ring
imidazole antifungals are not as broad spectrum as triazole antifungals
Imidazole general use: dermatophytosis and candida
clotrimazole
imidazole antifungal
not the usual structure
Ketoconazole
imidazole antifungal
use: dermatophytosis, blastomycosis, coccidiomycosis, candida
has more drug interaction because of its long tail
has less specificity, therefore may bind human CYP
It is a substrate for CYP 3A4
ADR: gynecomastia, lower libido, impotence, adrenal insufficiency, rash, elevated hepatic transaminases, QT prolongation
DDI: antacid, PPI, H2 blocker, sucralfate, isoniazid, phenytoin, phenobarb, rifampin, rifabutin (these drugs lower azole plasma levels)
Take antacid two hours before/after azole
Fluconazole
triazole antifungal - all except aspergillosis
general structure: triazole ring, di-halogenated ring
ADR: elevated hepatic transaminase, rash, hepatotoxic, neurotoxicity, QT prolongation
DDI: phenytoin, phenobarb, rifampin (these drugs lower azole plasma levels).
notice there is no DDI with antacid, PPI, or H2 blocker
Voriconazole
triazole antifungal
ADR: hepatotoxicity, renal toxicity (if given IV), CNS, photopsia (eye ADR), rash, QT prolongation
strongest CYP inhibitor!!
itraconazole
triazole antifungal
more toxic and more active because of long tail
has less specificity, therefore may bind human CYP
Major substrate and inhibitor of CYP 3A4
ADR: elevated hepatic transaminase, mineralcocorticoid excess, hypokalemia, pedal edema, HTN, rash, GI upset, cardiomyopathy
DDI: antacid, PPI, H2 blocker, sucralfate, carbamazepine, isoniazid, phenytoin, phenobarb, rifampin, rifabutin (these drugs lower azole plasma levels)
Take antacid two hours before/after azole
posaconazole
triazole antifungal - kills all
more toxic and more active because of long tail
has less specificity, therefore may bind human CYP
ADR: elevated transaminases, rash, hepatotoxicity, QT prolongation
DDI: antacid, PPI, H2 blocker, sucralfate, isoniazid, phenytoin, phenobarb, rifampin, rifabutin (these drugs lower azole plasma levels)
Take antacid two hours before/after azole
triazoles
vs
imidazole
triazole are more effective
have more dosage forms (oral and injectable)
treat all fungi EXCEPT Candida glabrata and Candida krueis
they are like amphoteracin B EXCEPT they are less toxic
Location of MOA: ergosterol synthesis pathway
MOA: block synthesis of ergosterol by prevent conversion of lanosterol to ergosterol (ergosterol is only present in fungi)
ALL AZOLES BLOCK 14-alpha-demethylase CYP
In order to make ergosterols in fungal cells…
you need
cholesterol
squalene oxidase
CYP demethylase
NADPH
FAD
porphyrin
iron
In order to get rid of a methyl group…
you must oxidize it three times
Three examples of CYP 3A4 inhibitors
mycin
protease
AZOLES especially fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole
absorption of azole is dependent on
acidity of gut
azoles are lipophilic amines so when they are in the upper GI, the acidity protonates the drugs which allows them to be better absorbed
drugs that have increased plasma levels when taken in conjunction with fluconazole, itraconazole, and ketoconazole
antihistamine
benzodiazepine
cisapride
cycloporine
corticosteroid
phenytoin
warfarin
statin (itraconazole only)
sulfonylurea (fluconazole and itraconazole only)
theophylline (fluconazole and ketoconazole only)
naftifine
allylamine
admin: oral
ADR: GI, rash, alter taste
Use: antifungal for ring worm
terbinafine
admin: oral
treatment lasts: 2-4 weeks
ADR: GI, rash, alter taste
CYP 2D6 inhibitor
Use: dermatophytes
NOT used on candida
griseofulvin
admin: oral
DDI: warfarin and oral contraceptives because it is a CYP inducer
Use: nail infection
treatment lasts 6-12 months for fingernail
treatment lasts 24 months for toenail
MOA: mitotic spindle inhibitor (prevents cell replication)
Caspofungin
Echinocandin family (micafungin, andulafungin)
admin: injection
Use: aspergillus and candida infection
ADR: hepatotoxicity, HSR, GI, CV (hypotension), respiratory distress, infusion reaction
it is a CYP substrate
rifampin, phenytoin and phenobarbital can induce the metabolism of caspofungin
MOA: inhibits glucan polymerization that is necessary for fungal cell to make cell wall
5 FC
target
resistance mechanism
target: RNA/DNA synthesis
resistance: mutation in transferase
nystatin and amphoteracin B
target
resistance mechanism
target: cell membrane ergosterol
resistance mechanism: introduction of low ergosterol content
terbinafine and naftifine
target
rsistance mechanisms
target: ergosterol biosynthesis
resistance mechanism: mutation in ABC transporters so drug concentration cannot be achieved in cell
