Pharmacology - Antifungal Agents Flashcards
Why is it difficult to develop antifungal drugs?
Fungi and humans are both eukaryotes
What is the important fungal steroid for plasma membranes? What does eliminating it do?
Ergosterol - fungal version of cholesterol
Elimination compromises fungal membrane integrity –> fungal cell death
What do imidazole and triazole work on?
14a-sterol demethylase
Inhibit lanosterol to ergosterol
Inhibit synthesis of ergosterol
What does echinocandins act on and what is its effect?
β-(1,3)-D-glucan synthase - inhibits cell wall synthesis
How is flucytosine taken up?
Taken up my cysteine specific permeases expressed only in fungal membrane
What does flucytosine act on?
Cystosine deaminase converts flucytosine to 5-FU
5-FU –> 5-FdUMP - inhibitor of thymidylate synthase (DNA synthesis and cell division)
What three agents is flucytosine used against?
Candidiasis
Cryptococcosis
Chromomycosis
What is the mechanism of griseofulvin?
Inhibits fungal mitosis by binding to tubulin & microtubule-associated proteins → disrupts assembly of mitotic spindles
What is the mechanism of squalene epoxidase?
Converts squalene to lanosterol → 1st key step of ergosterol synthesis
What three agents inhibit squalene epoxidase?
Terbinafine
Naftifine
Butenafine
Who is terbinafine contraindicated in?
Renal failure
Hepatic failure
Pregnancy
What enzyme do the -azoles work on?
14α-sterol demethylase → cytochrome P450 enzyme that converts lanosterol to ergosterol
Why is ketoconazole limited in use?
GI absorption issue
Adverse effects on metabolism of other drugs
Decreases steroid hormone synthesis
What has ketoconazole been replaced with?
Itraconazole
What are the two indications for topical ketoconazole?
Common dermatophyte infections
Seborrheic dermatitis
Why is fluconazole is the drug of choice for cryptococcal meningitis?
100% bioavailability
Absorption not influenced by gastric pH
Diffuses freely in CSF
Low adverse effects
What is the mechanism of action of polyene?
Binds to ergosterol ad produces channels/pores that allow leakage of essential cellular contents out of the cell → leads to cell death
What is the prototypic member of the polyene group and why is it selectively toxic?
Amphotericin B
Selective toxicity → affinity of amphotericin B for ergosterol is 500 times greater than its affinity for cholesterol
What is the immediate reaction to amphotericin B?
What are the four symptoms?
Cytokine storm → elicits release of TNF-α & IL-1
Symptoms → fever, chills, rigors, & hypotension
What are the three agents in the echnocandin class?
Caspofungin
Micafungin
Anidulafungin
