CP4 - Introduction to Antifungal agents Flashcards
what are the 3 classes of pathogenic fungi?
- filamentous fungi
- moulds/yeasts
- dimorphic - can exist in both forms depending on the conditions that they are exposed to
which type of fungi can cause disease?
microfungi
name some targets of antifungals
- DNA synthesis
- mitosis
- cell membrane
- protein synthesis
- cell wall
what is the main component of the cell membrane in humans and fungi?
humans - cholesterol
fungi - ergosterol
what is the main component of a fungal cell wall?
B-1,3-glucan
what is the function of ergosterol in fungal PM?
- regulates membrane permeability
2. important for the normal growth and function of the fungal cell wall
which 2 stages of ergosterol synthesis are attacked by drugs?
squalene –> lanosterole via squalene epoxidase
lanosterol –> ergosterol via lanosterol 14alpha demethylase
what are beta-1,3-glucans?
- large polymers of UDP-glucose
- form a large component of the fungus and its cell wall
- synthesised by B-1,3-glucan synthase
what are the classes of antifungals?
- polyenes
- Allylamines
- azaleas
- echinocandins
- others
name some examples of polyenes
amphotericin B
Nystatin
what is the mode of action of polyenes?
- associated with ergosterol
- form pore-like aggregations in the PM
- membrane loses its integrity and K+ leaks out of the cell, causing it to die
what is the spectrum of activity of amphotericin B?
most fungi of medical importance
what is the clinical use of amphotericin B?
Aspergillus candida
Cryptococcus
used for serious or systemic infections
parenteral administration
what are the adverse effects of polyenes?
- allergic reactions
- nephrotoxicity, due to a potential spillover effect on human membranes, usually to a lesser extent and reversible, but not used in patients with existing nephrotoxicity
what is the clinical use of nystatin?
only used for superficial infections, because it is not absorbed orally and is too toxic for systemic use.
oral.vaginal candidiasis
no systemic side effects
name an example of Allylamines
terbinafine
what is the mode of action of allylamines?
they stop ergosterol synthesis by inhibiting squalene epoxidase, therefore PM cannot form properly.
what is the spectrum of activity go allylamines?
broad spectrum in vitro
what is the clinical use of allylamines?
dermatophyte infections (superficial/topical use) 1. athlete's foot 2. tinea corporis 3. cruris systemic 1. scalp ringworm 2. onychomycosis
what are the adverse effects of allylamines?
liver toxicity, jaundice, hepatits, but this is rarely fatal
what are azoles?
synthetic compounds containing a 5 membered azalea ring
what are the 2 types of azoles?
- imidazole - 2 N atoms
2. triazoles - 3 N atoms
gives examples of imidazoles and triazoles
- imidazoles- clotrimazole, ketoconazole
2. triazoles - fluconazole, itraconzole, voriconazole
what is the mode of action of azoles?
inhibit ergosterol synthesis, leading to a build-up of monomers. fungus loses its viability because the PM cannot function
what is the spectrum of activity azoles?
together, azaleas cover all fungi. fluconazole is the only azole that is ineffective against aspergillus
what is the clinical use of imidazoles?
superficial infections -clotrimazole for candidiasis
what are the adverse effects of imidazoles?
toxic, rarely used systemically, they can cause life threatening hepatitis
what is the clinical use of triazoles?
systemic infections - aspergillosis, candidiasis (fluconazole), serous fungal infections
what are the adverse effects of triazoles?
less toxic, therefore systemic use is more common. can cause mild liver enzyme abnormalities
name some examples of echinocandins
anidulafungin
caspofungin
micafungin
what is the mode of action of echinocandins
inhibit B-1,3-glucan synthase, which is the main structural component of the cell wall. leads to a severely abnormal cell wall
what is the spectrum of actions of echinocandins?
aspergillus and candida, misses certain moulds and cryptococcus
what is the clinical use of echinocandins?
systemic infections, only available as IV
what are the adverse effects of echinocandins?
minimal. skin rash nausea vomiting headache this is due to a lack of B-1,3-glucan analogue in humans
what is 5-flurocytosine (5-FC)
a synthetic analogue of cytosine, a pyrimidine nucleoside
what is the mode of action of 5-fluorocytosine?
inhibits RNA/protein synthesis and DNA synthesis. it is selectively toxic because entry into the cell required fungal cytosine permease
what is the spectrum of activity of 5-fluorocytosine?
yeasts only, candida and cryptococcus
what is the clinical use of 5-fluorocytosine?
cryptococcal meningitis, in combination with Amphotericin B (only indication)
what is an adverse effect of 5-fluorocytosine?
can penetrate into human cells, but to a smaller extent. could cause bone marrow suppression
what is the mode of action of griseofulvin?
inhibits fungal mitosis
what is the spectrum of activity of griseofulvin?
dermatophytes
what is the clinical use of griseofulvin?
infections in children requiring systemic treatment, eg. scale infections
what are the adverse effects of griseofulvin?
minimal
what is a general adverse effect of azoles?
hepatotoxicity
what are the drug interactions of azoles?
inhibit cytochrome p450 enzyme, as a result,the concentration of all drugs metabolised by this enzyme increases
which fungi are fluconazole, itra/voriconazole and posa/isavuconazole effective against?
- yeasts only
- yeasts and aspergillus
- yeasts, aspergillus and mucoraceous moulds
why is therapeutic monitoring of drugs necessary?
- to minimise toxicity
2. to maximise efficacy
which antifungals require TDM?
- intraconazole
- 5-flurocytosine
- voriconazole
