Anti fungal drugs that target inhibition of ergosterol

Question 1

what class of drugs targets inhibition of ergosterol thru C14a demethylase inhibitors?
what is the class broken down in to (2)?

Answer 1

Azoles

Triazoles and Imidazoles

Question 2

Azoles
Broad or narrow spectrum?
Cidal or static?

Answer 2

Azoles are BROAD Spectrum
Static at low concentrations
cidal at high concentrations

Question 3

Azoles MoA to interfere with ergosterol synthesis is how?

Answer 3

Azoles bind through ring nitrogen to heme of cytochrome P450 and inhibit the lanosterol C14 demethylase system - fungistatic activity

Question 4

What is the selectivity of azoles?

what is more selective triazoles or imidazoles?

Answer 4

Azoles 100x more selective to fungal cell lanosterol C14 demethylase compared to mammalian enzyme
Triazoles are more specific than imidazoles

Question 5

what are 3 actions of azoles in their inhibition of ergosterol synthesis?
static or tidal activity by these 3 things?

Answer 5

1. alterations of FAs metabolism
2. accumulation of toxic peroxides, inhibition of respiration
3. alteration of Na/ K atpase, altering membrane fluidity
   these 3 activities are tidal

Question 6

What are the drug to drug interactions of Azoles

Answer 6

inhibitors of liver P450 enzymes leads to PK effects, and cardio effects

Question 7

What is the resistance mechanism of azoles

Answer 7

overproduction/ mutation of C14 demethylase, drug efflux

Question 8

What is an examples of a imidazole that was the first oral antifungal

Answer 8

ketoconazole

Question 9

ketoconazole
absorption:
route of admin:
this drug is consider a what based on that fact that it requires low pH in the stomach

Answer 9

ketoconazole
variable absorption
taken orally and topically
pH DEPENDENT DRUG!

Question 10

Ketoconazole is used to treat what

Answer 10

mucocutaneous candiasis
candiasis of mouth, esophagus, vagina
systemic candiasis

Question 11

Ketoconazole is ____ so its actions of interfered with by what?

Answer 11

Ketoconazole is PH DEPENDENT so Anti acids interfere with its absoprtion

Question 12

Ketoconazole is a what?
its metabolism and excretion is what?
its toxicity is what?

Answer 12

Ketoconazole is a imidazole
metabolism: P450 liver metabolism, small amount excreted in urine and bile, mainly protein bound
toxicity is GI

Question 13

Name the 2 pH Dependent Triazoles

Answer 13

Itraconazole

Posaconazole

Question 14

Name the 3 ph INDEPENDENT triazoles

Answer 14

Efinaconazole
fluconazole
voriconazole

Question 15

Fluconazole is a pH what?
used to tx what?
taken how?

Answer 15

Fluconazole is pH INDEPENDENT
taken orally to treat dermatomycoses
tx for oropharyngeal and vaginal candiasis

Question 16

what is Fluconazole used for in AIDS pts to allow outpatient tx

Answer 16

Fluconazole is used for tx of cryptococcal meningitis in AIDS pts

Question 17

fluconazole
metabolism/ excretion:
Toxicity:
Resistance:

Answer 17

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

Question 18

Efinaconazole is a pH what?
used for? used how?
MoA
Toxicity?
Most related in structure to what drug?

Answer 18

Efinaconazole is pH INDEPENDENT
used topically for onchomycosis (nails)
Inhibits C14 demethylase
Toxicity: application site dermatitis
Structurally similar to voriconazole

Question 19

Posaconazole 
pH what?
taken how?
broad or narrow spectrum?
tx for what?

Answer 19

Posaconazole
pH DEPENDENT!!
taken oral, BROAD spectrum
tx for aspergillosis, candiasis

Question 20

Posaconazole
MoA
Toxicity
Special note of drug interactions

Answer 20

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

Question 21

What is the special note about the MoA of posaconazole, a pH dependent triazole

Answer 21

Posaconazole inhibits C14 demethylase isoforms CYP1A and CYP51B in aspergillus

Question 22

Voriconazole pH what?
taken how to treat what?
does it affect CNS? how?

Answer 22

Voriconazole is pH INDEPENDENT!!
taken orally and IV to treat INVASIVE ASPERGILLOSIS
Crosses the BBB so it effects CNS

Question 23

Voriconazole
absorption and distribution:
Metabolism/ excretion:
Toxicity:

Answer 23

Voriconazole
absorption: oral pH independent
metabolism by liver, excreted in urine
toxicity: hepatoxicity and visual hallucinations (transient)

Question 24

Voriconazole requires special care with other drugs why?

Answer 24

Voriconazole has multiple drug to drug interactions with substrates/ inhibitors of P450s

Question 25

What is a special toxicity of Voriconazole

Answer 25

Voriconazole can cause visual transient hallucinations

Question 26

Itraconazole is pH what?

taken how? to treat what

Answer 26

Itraconazole is pH DEPENDENT, requires low stomach pH!!!

taken oral or IV to treat histoplasmosis, blastocycosis, aspergillosis

Question 27

comparing itraconazole to ketoconazole which one has broader spectrum?

Answer 27

Itraconazole has Broader spectrum than ketoconazole

Question 28

Itraconazole
metabolism:
Toxicity:
Drug to drug interactions:

Answer 28

itraconazole
metabolism by liver, excreted in bile
Hepatotoxicity and GI distress
Drug to Drug: Substrate inhibitor of P450s so multiple interactions

Question 29

what two triazoles have the highest drug to drug interactions? why?

Answer 29

Itraconazole and Voriconazole have multiple drug to drug interactions bc they are both affected by substrates/ inhibitors of P450s