Anti fungal drugs that target inhibition of ergosterol Flashcards
what class of drugs targets inhibition of ergosterol thru C14a demethylase inhibitors? what is the class broken down in to (2)?
Azoles
Triazoles and Imidazoles
Azoles
Broad or narrow spectrum?
Cidal or static?
Azoles are BROAD Spectrum
Static at low concentrations
cidal at high concentrations
Azoles MoA to interfere with ergosterol synthesis is how?
Azoles bind through ring nitrogen to heme of cytochrome P450 and inhibit the lanosterol C14 demethylase system - fungistatic activity
What is the selectivity of azoles?
what is more selective triazoles or imidazoles?
Azoles 100x more selective to fungal cell lanosterol C14 demethylase compared to mammalian enzyme
Triazoles are more specific than imidazoles
what are 3 actions of azoles in their inhibition of ergosterol synthesis?
static or tidal activity by these 3 things?
- alterations of FAs metabolism
- accumulation of toxic peroxides, inhibition of respiration
- alteration of Na/ K atpase, altering membrane fluidity
these 3 activities are tidal
What are the drug to drug interactions of Azoles
inhibitors of liver P450 enzymes leads to PK effects, and cardio effects
What is the resistance mechanism of azoles
overproduction/ mutation of C14 demethylase, drug efflux
What is an examples of a imidazole that was the first oral antifungal
ketoconazole
ketoconazole
absorption:
route of admin:
this drug is consider a what based on that fact that it requires low pH in the stomach
ketoconazole
variable absorption
taken orally and topically
pH DEPENDENT DRUG!
Ketoconazole is used to treat what
mucocutaneous candiasis
candiasis of mouth, esophagus, vagina
systemic candiasis
Ketoconazole is ____ so its actions of interfered with by what?
Ketoconazole is PH DEPENDENT so Anti acids interfere with its absoprtion
Ketoconazole is a what?
its metabolism and excretion is what?
its toxicity is what?
Ketoconazole is a imidazole
metabolism: P450 liver metabolism, small amount excreted in urine and bile, mainly protein bound
toxicity is GI
Name the 2 pH Dependent Triazoles
Itraconazole
Posaconazole
Name the 3 ph INDEPENDENT triazoles
Efinaconazole
fluconazole
voriconazole
Fluconazole is a pH what?
used to tx what?
taken how?
Fluconazole is pH INDEPENDENT
taken orally to treat dermatomycoses
tx for oropharyngeal and vaginal candiasis
what is Fluconazole used for in AIDS pts to allow outpatient tx
Fluconazole is used for tx of cryptococcal meningitis in AIDS pts
fluconazole
metabolism/ excretion:
Toxicity:
Resistance:
Fluconazole
Metabolism/ excretion: no metabolism excreted unchanged in feces and urine
toxicity: low, some GI upset, nausea, INC hepatic enzymes
resistance: altered demethylase enzyme, and INC efflux
Efinaconazole is a pH what? used for? used how? MoA Toxicity? Most related in structure to what drug?
Efinaconazole is pH INDEPENDENT used topically for onchomycosis (nails) Inhibits C14 demethylase Toxicity: application site dermatitis Structurally similar to voriconazole
Posaconazole pH what? taken how? broad or narrow spectrum? tx for what?
Posaconazole
pH DEPENDENT!!
taken oral, BROAD spectrum
tx for aspergillosis, candiasis
Posaconazole
MoA
Toxicity
Special note of drug interactions
Posaconazole
MoA: Inhibits C14 demethylase isoforms CYP1A and CYP51B in Aspergillus
Toxicity: Hepatotoxicity, Thrombocytopenia
Special Note: few interactions with P450s and few drug to drug interactions
What is the special note about the MoA of posaconazole, a pH dependent triazole
Posaconazole inhibits C14 demethylase isoforms CYP1A and CYP51B in aspergillus
Voriconazole pH what?
taken how to treat what?
does it affect CNS? how?
Voriconazole is pH INDEPENDENT!!
taken orally and IV to treat INVASIVE ASPERGILLOSIS
Crosses the BBB so it effects CNS
Voriconazole
absorption and distribution:
Metabolism/ excretion:
Toxicity:
Voriconazole
absorption: oral pH independent
metabolism by liver, excreted in urine
toxicity: hepatoxicity and visual hallucinations (transient)
Voriconazole requires special care with other drugs why?
Voriconazole has multiple drug to drug interactions with substrates/ inhibitors of P450s
What is a special toxicity of Voriconazole
Voriconazole can cause visual transient hallucinations
Itraconazole is pH what?
taken how? to treat what
Itraconazole is pH DEPENDENT, requires low stomach pH!!!
taken oral or IV to treat histoplasmosis, blastocycosis, aspergillosis
comparing itraconazole to ketoconazole which one has broader spectrum?
Itraconazole has Broader spectrum than ketoconazole
Itraconazole
metabolism:
Toxicity:
Drug to drug interactions:
itraconazole
metabolism by liver, excreted in bile
Hepatotoxicity and GI distress
Drug to Drug: Substrate inhibitor of P450s so multiple interactions
what two triazoles have the highest drug to drug interactions? why?
Itraconazole and Voriconazole have multiple drug to drug interactions bc they are both affected by substrates/ inhibitors of P450s
