Core pharmacology

Class Group

Antifungal

Legacy Cicm Level

Level 3

Introduction

Triazoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole
Imidazoles: Clotrimazole, Ketoconazole

Mechanism of action

Azoles disrupt ergosterol production by interacting with 14-alpha demthylase, a cytochrome P450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of fungal cell membranes, inhibition of its synthesis leads to increased cell permeability causing leakage of contents.

Antimicrobial Spectrum

Fluc: Candida
Cryptococcus
Coccidia
(No activity against histoplasma, blasto, sporotrichosis, Aspergillus, mucormycosis)

Resistance Mechanism

Fluc: Some candida species,

Decreased drug concentration
Target site alteration
Up-regulation of target enzyme
Development of bypass pathways

Adverse Effects Toxicity

Fluc: N/V/D, Abdominal pain
Headache
Skin rash
Reversible alopecia
Rare: Hepatic failure, SJS
Should be avoided in Pregnancy
Drug interactions: (inhibitor of CYP3A4, CYP2C9)

Absorption

Well absorbed orally (except miconazole)

Distribution

Fluc – good CSF penetration
Itra, Keto – no CSF penetration

Protein binding

Itra, Keto – 99% PB

Metabolism

Fluc not metabolized well
Itra, Keto – metabolized by liver

Excretion

Fluc – Urine unchanged
Itra, Keto – Excreted bile

Special Points

potent CYP inhibitors with a wide range of drug interactions (including warfarin)