Week 11 - Antifungal Drugs Flashcards
What types of fungal infections/Mycoses are there?
- superficial (e.g. Scalp, mucous membranes)
- systemic (internal organs - kidneys, lung and brain, fatal in severely immunocompromised patients)
What are fungal pathogens and what category of pathogens do they belong too?
Eukaryotes
- commensal
- environmental
-category of opportunistic infections
What are the most common opportunistic fungal pathogens?
- Candida albicans (commensal)
- aspergillus fumigatus (environmental)
- cryptococcus neoformans (environmental)
What puts patients at a higher risk of developing fungal infections?
Impaired immune system
-HIV, organ transplantation, a course of long term broad-spectrum abx, premature birth, cancer, hospitalisation in ICU
Menstrual cycle in women
What do anti-fungal drugs target?
Fungal-specific processes/structures
How are fungal cells structured?
Fungal cells have:
- cell wall
- plasma membrane
- nucleus -DNA and RNA synthesis
What is the difference between fungal and human cells?
They have a cell wall
- crucial for survival of the cell
- complex structure and composition
- no equivalent organelle in human cells
-ideal target for antifungals
What does a fungal cell wall have and what is it made up of?
- skeletal components
- matrix components
-glucan (55-60%) of the cell wall
(two types of polymers of D-glucose - B1,6 glucan and B1,3 glucan)
- mannan (35-50%) - glycosylated proteins (mannoproteins)
- chitin (2% of the cell wall)
Name some echinocandins and what their mechanism of action is
- caspofungin, micafungin
1. inhibit the enzyme B1,3 glucan synthetase
2. Block synthesis of B1,3 glucan
3. Fungicidal effects
What is the target of most of the currently used antifungals?
The plasma membrane
What is the difference between plasma membranes in human and fungal cells?
Human PM’s - contain cholesterol
Fungal PM’s - ERGOSTEROL
- ergosterol = an essential component of fungal plasma membranes
- in the absence of functional ergosterol biosynthesis - fungal cells cannot grow and survive
What is the mechanism of action of antifungals that target ergosterol?
Either
-bind to resident ergosterol in the plasma membrane
OR
-inhibit different ergosterol biosynthetic enzymes and block de novo biosynthesis of ergosterol
What are the types of drugs that target ergosterol?
- polyene antifungals
- azoles
- allylamines
What is the mechanism of action of polyene antifungals?
-fungicidal
- bind to ergosterol
- and form pores in the plasma membrane which disrupt membrane integrity causing leakage of cell constituents
-higher affinity for ergosterol than cholesterol
What side effects of polyene antifungals are associated with prolonged application?
-severe side effects - kidney failure
Name some polyene antifungals, what they are used for and side effects if any
Amphotericin B (Prolonged use has severe side effects)
Nystatin
(Used in treatment of oral and GI fungal infections)
-both natural in origin
What reduces the risk of side effects after prolonged use of Amphotericin B
Prolonged use has severe side effects BUT
Amp B lipid complex (ABLC)
and
liposomal Amp B (L-Amp B) formulations reduce the risks
What is a key step in ergosterol biosynthesis?
Lanosterol demethylation
What is the mechanism of action of azoles?
- ergosterol biosynthesis inhibitors
- inhibit the enzyme Lanosterol C-14 demethylase
(Blocks ergosterol biosynthesis, leads to accumulation of toxic intermediates, causes growth arrest)
What are the two types of azole antifungals?
Imidazoles
Triazoles
Name some imidazoles
Miconazole
Clotrimazole (canesten)
Ketoconazole
Name some examples of Triazoles
Fluconazole
Voriconazole
Itraconazole
What type of antifungals are the azoles (imidazoles and Triazoles)?
Fungistatic
-inhibit the enzyme Lanosterol C14-demethylase
Why are Triazoles more potent antifungals than imidazoles?
They have a higher affinity for the enzyme Lanosterol C14-demethylase
Hence more potent
What is the mechanism of action of allylamines?
Inhibits ergosterol biosynthesis
Inhibit an earlier step before the step azoles inhibit
Name some allylamines
Terbinafine
Amorolfine
Which drug inhibits fungal DNA and RNA synthesis?
Flucytosine
What is Flucytosine’s mechanism of action?
-inhibits fungal DNA + RNA synthesis
- Taken up by fungal cells
- Metabolised by fungal cells to 5-fluoroacil (5-FU)
- 5-FU is a toxic antimetabolite
- 5-FU inhibits DNA and RNA synthesis
-associated with high levels of resistance
What is Flucytosine usually used in combination with?
Azoles
What are fungal diseases also known as?
Mycoses
