Antifungal Drugs Flashcards
What are the main targets of antifungal drugs in fungi?
(These are components of fungi)
- Ergosterol:
predominent component of fungal cell membrane ( bioregulator of membrane fluidity, asymmetry and integrity ) - Microtubules:
part of cytoskeleton, inside they have mitotic spindles needed for cell reproduction. Forms cilia and flagella - 1,3-β-glucan:
polysaccharide component of fungal cell wall. - DNA.
What is the mechanism of action of Amphotericin B ( a polyene) ?
Polyenes bind to ergosterol in final cell membranes = forming large pores = disrupting ion balance = causing unregulated leakage of ions and metabolites = loss of ion balance = fungal cell death
What is the spectrum of activity of Amphotericin B ?
It is active against most fungi & yeasts
Amphotericin enhances the effects of what other antifungal drug ?
Flucytosine
How is Amphotericin B administered ?
Due to poor oral absorption, it is given either topically or IV if systemic infection.
What are the side effects of Amphotericin B ?
- renal toxicity
- impaired hepatic function
- Neurotoxicity
- skin rash with topical application
What is flucytosine
A synthetic, orally active pyrimidine antimetabolite
What is the mechanism of action of flucytosine?
Flucytosine → 5 fluorouracil → 5-fluorodeoxyuridylic acid (5-FdUMP) =
Inhibits thymidylate synthetase = INHIBITS DNA SYNTHESIS
ALSO
Fluorouridinetriphosphate (5-FUTP) = incorporated into fungal RNA = DISRUPTS PROTEIN SYNTHESIS
Why is Flucytosine often combined with Amphotericin B ?
- Due to the rapid development of resistance to Flucytosine
- they act synergistically since Amphotericin B affects cell permeability = ↑ more Flucytosine can penetrate the cell
- used to treat systemic infections
What systemic infections are treated with the combination of Flucytosine and Amphotericin B ?
Candidiasis
Cryptococcal meningitis
What are the side effects of Flucytosine ?
Rare side effects but they include :
- GI disturbances
- anemia
- neutropenia
- thrombocytopenia
These effects stop after discontinuation of drug
What is the mechanism of action of Azoles ?
Inhibits the conversion of Lanosterol to Ergosterol by inhibiting the enzyme Lanosine 14α-demethylase (fungal cytochrome P450 3A enzyme)
So …. Depletion of ergosterol = changes in cell membrane fluidity and changes in function of membrane proteins
How does Azoles mechanism of action impact the effects of Amphotericin B?
Depletion of ergosterol = reduces binding sites for amphotericin B.
What is the 1st Azole given orally to treat systemic fungal infections?
Ketoconazole
What are the side effects of ketoconazole ?
- hepatotoxicity
- GI disturbances
- Pruritus
- endocrine effects : gynecomastia in male patients (because it inhibits adrenocortical steroid and testosterone synthesis at high doses)
What is the mechanism of action of Terbinafine ?
Inhibits the enzyme squalene epoxidase, which is involved in the synthesis of ergosterol from squalene (so not enough ergosterol for the cell membrane)
AND
This accumulation of squalene in the cell is toxic to fungi
What are the clinical uses of terbinafine ?
Orally used to treat ringworm (dermatophytosis)
Fungal infections of the nails
What are the side effects of terbinafine ?
Rare and generally mild side effects:
- GI disturbances
- headache and dizziness
What is the mechanism of action of Griseofulvin ?
Enters cells by an energy-dependent process → interacts with fungal microtubules → disrupting the mitotic spindle = INHIBITING MITOSIS
True or false
Griseofulvin treatment should be prolonged in order to be effective
True
True or false
Griseofulvin is not used as often as it used to be
True
What are the side effects of Griseofulvin?
Allergic reactions
Teratogenic (should not be given to pregnant women)
Why should griseofulvin not be given to pregnant women?
Griseofulvin is teratogenic and can cause harmful effects during pregnancy as it can disrupt the growth and development of the embryo/fetus
What is the mechanism of action of echinocandins?
Inhibit the synthesis of 1,3-β-glucan, a glucose polymer essential for maintaining the structure of the fungal cell wall = leading to CELL LYSIS.
