INHIBITORS OF SQUALENE EPOXIDASE: ALLYLAMINES AND BENZYLAMINES

Question 1

Allylamines (squalene epoxidase inhibitors)

Mechanism of effect:

Answer 1

squalene → ergosterol conversion is inhibited → squalene accumulation → fungicidal

1. squalene
   - squalene - epoxidase
2. lanosterol
3. ergosterol

• they prevent the formation of lanosterol
• accumulation of the toxic metabolite squalene
• spectrum: broad, dermatophytes + yeasts

Question 2

Allylamines

Answer 2

Terbinafin (AA) ( Lamisil ® , Terbisil ® )
oral/ topical administration: dermatomycosis, onychomycosis
Microsporum spp., Trichophyton spp., Candida spp., Malassezia spp.
– kidney-, liver tox, pregnancy
– mild-moderate hepatotoxicity (itraconazol)
– accumulates in the skin and nails (≈griseofulvin)

Naftifine (AA)
– broad spectrum – topical administration: in gel or in ointment
– Th: dermatomycosis és onychomycosis

Question 3

Inhibitors of 14α-Sterol Demethylase Imidazoles and Triazoles
Azoles

Answer 3

Mechanism of effect:
membrane disruption: conversion of lanosterol → ergosterol is inhibited ( 14 - α - sterol - demethylase inhibitors )
selective toxicity, but…!!

Question 4

Imidazoles and Triazoles

Answer 4

Spectrum: dermatophytes + yeasts ( Malassezia spp. very sensitive!)
Kinetics: following local administration only the corium can be reached, maybe subcutaneous tissue, absorption <2%
Imidazoles

thiabendazole 
clotrimazole 
enilconazole
miconazole 
bifonazole
ketoconazole

Triazoles
itraconazole
 fluconazole
posaconazole
voriconazole

Question 5

IMIDAZOLES- Ketoconazole

Answer 5

– local or systemic
– broad spectrum against dermatophytes and yeasts
– little penetration into the CSF and urine
– approx in 20%: nausea, vomiting
– hepatotox!
– CYP 450 inhibitor
– Cushing syndrome

Question 6

IMIDAZOLES - Enilconazole

Answer 6

(Imaverol suspension A.U.V.)
local
narrow spectrum: mainly dermatophytes (Malassezia resistant)

Question 7

IMIDAZOLES

clotrimazole, miconazole, bifonazole + thiabendazole

Answer 7

clotrimazole, miconazole, bifonazole
Th: superficial fungal infections against Malassezia spp. active ingredient of ear drops, shampoo, and topical solutions

thiabendazole
Th: M. pachydermatis- caused external otitis

Topical azoles are generally not effective against hair or nail fungal infections, and topical azoles should not be used to treat subcutaneous or systemic mycoses.

Question 8

TRIAZOLES
itraconazole
posaconazole

Answer 8

itraconazole
– Th: aspergillosis, blastomycosis and histoplasmosis – in case of meningitis
– hepatotox< compared to ketoconazole
– feline: 1 week T+1 weeks DH 3 times

posaconazole
– itraconazole derivative
– effective against yeasts and dermatophytes
– in ear drops

Question 9

TRIAZOLES voriconazole ; fluconazole

Answer 9

voriconazole -systemic Aspergillus

fluconazole
– expensive
– hydrophilic, iv and oral
– BA: 100%, gastric pH does not influence absorption
– diffuses freely into CSF, sputum, urine, and saliva
– elimination: kidney

Question 10

LOCAL TREATMENT Imidazoles and Triazoles

Answer 10

-Thiabendazole
( Dexoryl ear drop A.U.V.) effective against Malassezia pachydermatis (external otitis)
-Clotrimazole broad spectrum: yeasts and dermatophytes
-Miconazole broad spectrum: yeasts and dermatophytes
-Enilconazole narrow spectrum: mainly dermatophytes ( Malassezia resistant)
-Bifonazole
-Ketoconazole broad spectrum: yeasts+ dermatophytes
-Posaconazole ( Posatex ear drop )

Question 11

SYSTEMIC TREATMENT Imidazoles and Triazoles

Answer 11

Itraconazole ( Itrafungol A.U.V .)
Fluconazole
Voriconazole
Ketoconazole (?)

Question 12

LOCAL TREATMENT-OTHERS

Answer 12

• tolnaftate ( Digifungin ® , Athlete’s Foot ® )
• hexachlorophen
• chlorhexidine
• benzoic acid
• salicylic acid
• dyes (fuchsine, resorcine, acriflavine)