Antifungal Drugs Flashcards
4 main classes of antifungal drugs + spectrum and toxicity
1) polyenes; broad spectrum, fungicidal, high systemic toxicity
2) azoles; broad spectrum, fungistatic, very low toxicity
3) pneumocandins and echinocandins; low toxicity
4) drugs used to treat dematophytosis
example of a polyenes
amphotericin B
example of azoles
itraconazole
example of pneumocandins
caspofungin
example of a drug used to treat dermatophytosis
terbinafine
fungi are _____, which makes them harder/easier to attack without affecting host
eukaryotic
harder
3 main targets of antifungal drugs
-plasma membrane (most systemic drugs, polyenes, azoles)
-cell wall (pneumocandins)
-protein synthesis, nucleic acid synthesis (flucytosine)
what does the plasma membrane in fungi contain instead of cholesterol
ergosterol…. target of many antifungals
mechanism of polyenes
Polyenes bind ergosterol in fungal membrane -> inserted into membrane -> several molecules come together to form a pore -> pores cause fungal cell to lyse (fungicidal)
amphotericin B; route of administration, distribution, how to improve solubility, half life, spectrum
-Conventional amphotericin B is usually formulated with bile salts to improve solubility, however can cause adverse effects
-Poor oral absorption; usually given IV
-Distributes to extracellular fluid; poorly into CNS
-long half life
-broad spectrum…. greater than the azoles
clinical uses of amphotericin B (systemic and topical)
-Systemically, main use is in dogs & cats with life-threatening systemic mycoses, esp. in immunocompromised patients due to the fungicidal nature of the drug
-Topical administration in most species
adverse effects of amphotericin B
how to make safer
-Main adverse effect is dose dependent nephrotoxicity seen primarily with bile salt formulations
-IV admin should be slow (4-6 h)
-Lipid-complex formulations are much safer
what is the most toxic antimicrobial drug in clinical use
amphotericin B
azoles; spectrum, oral bioavailability,
-broad spectrum, funigstatic
-good oral bioavailability
-generally safe, though teratogenic
azoles drugs for systemic vs topical use
-For systemic use, older imidazoles
(e.g., ketoconazole) are usually less effective and are more toxic than newer triazoles (e.g., itraconazole)
-For topical use, imidazoles & triazoles are often interchangeable (good efficacy, low toxicity)
mechanism of action for azoles
Azoles inhibit mammalian hepatic
P450 enzymes -> inhibits metabolism of many concurrently administered drugs
what is a common adverse effect of systemic therapy with imidazole
endocrine adverse effects
Inhibit mammalian sterol synthesis (esp. cortisol & testosterone)
types of triazoles (3), safety, half lives
Fluconazole
Itraconazole
Voriconazole
-Less effect on mammalian sterol
synthesis -> generally very safe
-Longer half-lives than imidazoles
types of imidazoles (systemic and topical)
Systemic: Ketoconazole
Topical: Clotrimazole, enilconazole,
miconazole
what is an example of use of ketoconazole
Sometimes used in the management of hyperadrenocorticism because of its ability to inhibit cortisol synthesis (a use unrelated to its antifungal properties)
itraconazole; spectrum, absorption, adverse effects, contraindication
-fairly broad spectrum
-good oral absorption
-no adverse effects on mammalian steroid synthesis
-contraindicated in pregnancy = teratogenic effects
mechanism of action for caspofungin
inhibits fungal cell wall synthesis
but expensive and no animal data
mechanism of action of terbinafine
Mechanism: inhibits ergosterol synthesis in virtually all dermatophytes (and several other types of fungi)
Toxic metabolites accumulate -> fungicidal
adverse effects of terbinafine
- Low incidence of adverse effects in dogs & cats-> well tolerated even for prolonged therapy (60 days)
- May see GI upset; nausea & vomiting may indicate hepatic injury;
rare but severe skin problems - Inhibits some hepatic P450 enzymes -> consider in animals receiving other drugs metabolized in the liver
treatment against candida albicans
-Topical azole or polyene if
lesions accessible
-Systemic azole or polyene +/-
other
treatment against aspergillus fumigatus
Topical azole or polyene if lesions
accessible (e.g., clotrimazole or enilconazole)
-Systemic: Polyene or azole +/- other
treatment against blastomyces dermatitidis
-May require combined amphotericin B + azole
-Often requires prolonged treatment if established
-Often combine with anti- inflammatory therapy for tx of fungal pneumonia, otherwise dead fungal cells trigger pulmonary inflammatory reaction that can be fatal
