15. Antifungals Flashcards
What are fungal infections?
What do antifungals do?
Tend to be less serious than bacterial infections (some exceptions)
Many fungal infections develop/grow slowly, and some affect tissue such as skin and nails
Many anti fun gals are available without a prescription
Antifungals damage cell wall/membrane
Cell wall synthesis inhibitors
Ergosterol inhibitors
What do fungal cell wall synthesis inhibitors do?
Fungal cells have both a cell wall and a cell membrane
Glucan provides structural rigidity to this cell wall (glucan synthesized by glucan synthase)
Glucan synthase inhibitors prevent glucan from providing rigidity to this cell wall, causing cell lysis
These are echinocandins (caspofungin)
Well tolerated, must be injected
How do antifungals target the cell membrane?
Target critical components of the membrane
Fungi have egrosterol in their cell membrane, instead of cholesterol
Inhibiting egrosterol causes membrane disruption and cell lysis
Inhibit enzymes that produce ergosterol
Inhibit CYP450 enzymes
Bind directly to ergosterol (polyenes)
Humans have cholesterol in their cell membrane, selective for fungal versus human CYP450
Slide 12-21
What are squalene epoxidase inhibitors?
Terbinafine
Inhibit enzymes that produce ergosterol
Also result in a buildup of squalene which is also toxic to cell
Side effects: hepatotoxicity, serious rash, neutropenia
Slides 13-15
What are azole antifungals?
Clotrimazole
Inhibit enzymes that produce ergosterol
Inhibit CYP450 enzymes
CYP inhibitor will reduce clearance of other drugs that are substrates for that isozyme, results in decreased metabolism of drug A and increased levels of drug A in body
Slides 16-17
What are polyenes?
Amphotericin B
Bind directly to ergosterol (form a film around ergosterol and cause membrane destabilization)
Most toxic of all the ergosterol inhibitors
Reserved for serious fungal infections
Side effects: nephrotoxicity
Nystatin
Used to treat thrush (fungal infection in mouth)
Slides 18-20
How do antifungals inhibit DNA?
What drug does?
Inhibit nucleic acid synthesis
Antimetabolite- flucytosine
Inhibits DNA synthesis by creating false nucleotide that cannot be incorporated into DNA
Enters fungal cell with help from permease enzyme
Side effects: bone marrow suppression (leukopenia), GI (nausea, vomiting, diarrhea), rash
Slides 22-24
How do antifungals inhibit microtubules?
What drug does this?
Griseofulvin inhibits cell division by interfering with microtubules function, inhibits microtubules by preventing their polymerization
Side effects: hepatotoxicity, hematologic toxicities (leukopenia, neutropenia)
Slides 25-27
What antifungals are used for infections caused by candida (vaginal yeast infections, oral thrush, skin infections)?
What antifungals are used for inside of mouth?
A number of antifungals are used topically for infections caused by candida
For infections on inside of mouth, drugs with limited bioavailability are used
What is the resistance mechanism enzyme inhibitors?
Alterations in target site for enzyme
Enzyme inhibits produce more enzymes (glucan synthase inhibitors)
Upregulate genes that produce glucan synthase
Slides 31-33
What is the resistance mechanism drugs that act intracellularly?
Prevent entry of a drug into cell
Ex: flucytosine requires enzymes called permeases to gain entry to the cell, alterations in order he permeases can prevent entry of flucytosine into the cell
Pump drug out using efflux pumps (multi drug resistant transporter)
Slides 34-36
What could fungi do to survive an attack from an ergosterol inhibitor?
Make more ergosterol
Increased gene expression
Create an alternative to ergosterol
14-methylecosterol
What is the reaction mechanism inactivating the drug molecule?
Instead of creating enzymes that attack the drug molecule, fungi will often trap they drug molecule, preventing it from reaching its target
Ex: echinocandins need to reach the cell membrane in order to inhibit glucan synthase
Fungi use biofilms to trap the echinocandins in the cell wall, preventing them from reaching cell membrane
What is antifungal combination therapy?
Combination therapy is typically reserved for serious fungal infections
Most established combination used is amphotericin B with flucytosine
Amphotericin B opens up pores in the cell membrane, facilitating entry of flucytosine into the fungal cell
Amphotericin B with azole antifungals has had mixed results (sometimes even reducing eachother activity) because azole antifungals reduce the formation of ergosterol and ergosterol is the target for polyenes
Slides 41-44
