Mechanism of Action of Anti-Fungal Drugs Flashcards
What are the main classes of yeast fungi that infect humans and the disease entities they cause?
- candida spp (thrush, fungaemia - in immunocompromised)
- cryptococcus neoformans (meningitis, pneumonia, fungaemia)
- pityriasis versicolor (chronic skin infection)
- systemic yeast eg. histoplasma capsulatum (pulmonary/disseminated infections)
What are the main classes of filamentous fungi that infect humans and the disease entities they cause?
- aspergillus spp. (mucor, rhizopius, absidia):
- pulmonary/ocular infection
- farmer’s lung
- allergic bronchopulmonary/ invasive aspergillosis
- aspergilloma
- dermatophytes (epidermophyton, microsporum, trichophyton): chronic infection of skin, naills, kerion
How is farmer’s lung caused?
- occupational health hazard
- working in agriculture
- inhaling organism doesn’t make you sick but immune response does (type III hypersensitivity)
What are the 3 manifestations of bronchopulmonary aspergillosis?
- can be inflammatory resulting in asthma
- can be invasive causing diffuse pneumonia if enters lung/septic infection if enters bloodstream
- can form aspergilloma (if another form of respiratory disease) - ball of fungal organisms which can cause catastrophic bleeding
What are the 4 different tri-azole drugs and what they are used to treat?
- fluconazole: fungal meningitis
- itraconazole: dermatophytes
- posaconazole: invasive fungal infections unresponsive to conventional treatment
- voriconazole: life-threatening infections
What are the key pieces of information to remember about fluconazole?
- can be taken orally
- has good penetration into CSF
- usually well tolerated but does have some side effect
- liver toxicity
Describe the mechanism of action of tri-azole drugs
- targets ergosterol biosynthetic pathway
- stops lanosterol from being converted to ergosterol by inhibiting 14 a-demethylase
How can resistance against fluconazole develop?
Organism can generate an efflux pump which can pump out the drug
What are the 2 polyene drugs and what are they used to treat?
- amphotericin: systemic fungal infections
- nystatin
What are the key pieces of information to remember about amphotericin?
- topical/IV administration
- poorly penetrated into body fluid and tissues
- high toxicity - can cause severe kidney problems
- lipid formulations significantly less toxic and are recommended when conventional formulation is contra-indicated due to toxicity/response to conventional amphotericin is inadequate
Describe the mechanism of action of polyenes
- it embeds itself into ergosterol components in fungal cell membrane inhibiting protein synthesis
- results in leakage of electrolytes causing the cell to die
What is flucytosine used for and what are the risks?
- used for systemic infections - serious fungal infections
- risk of significant toxicity in the bone marrow
- used in combination with other drugs usually amphotericin
Describe the mechanism of action of flucytosine and why it works well with amphotericin
- because amphotericin makes increases cell permeability by embedding and forming channel, it allows fluctytosine to enter cell
- it accumulates inside cell and acts as a false nucleotide and disrupts DNA replication process
What are examples of echinocandins and the fungi they are active against?
- anidulafungin
- caspofungin
- micafungin
- active against candida spp, aspergillus spp (but not used for aspergillosis)
Describe the mechanism of action of echinocandins
- inhibit beta-(1,3)-D-glucan synthase
- polysaccharide chain that forms across the top of the fungal cell membrane that prevents it from osmotic stress
- coating and strengthening component of cell membrane
What is terbinafine used for and what method of administration is it given by?
- dermatophyte/ringworm infections
- given topically
Describe the mechanism of action of terbinafine
- interferes with ergosterol synthetic pathway
- interferes with squalene epoxidase
- breaking down squalene into toxic products causing cell death
What is griseofulvin used for and what are the unwanted effects of it?
- dermatophyte infections where topical therapy has failed
- dyspepsia
- fatigue
- allergy
Describe the mechanism of action of griseofulvin
- causes disruption of the mitotic spindle which inhibits mitosis
- induces hepatic CYP450 enzymes
What are the different ways that resistance can occur?
- target enzyme overproduced so that drug does not inhibit biochemical reaction completely
- drug target altered so that drug cannot bind to target
- efflux pump
- cell has bypass pathway that compensates for loss-of-function inhibition due to drug activity
- some fungal enzymes convert inactive drug to active form inhibited
- cell secretes enzymes to extracellular medium that degrade drug
