Antifungals Flashcards
Amphotericin B
Polyene
Notes - Bind preformed ergosterol (cell membrane) & other sterols causing 1) membrane deformation 2) pore 3) leakage of K and Mg 4) metabolic derangement = cell lysis.
Used for serious systemic fungal infections by I.V, topically for mycotic corneal ulcers & keratitis. Amphotericin B is gold standard for common Candidas infections. Can’t use orally. Poor bioavailability bc 99% albumin bound. Half life 15 days, similar to terbinafine
CAN’T BE USED WITH AZOLES
S/E - short term -fever & chills (bc release ILs & TNFa), hypokalemia/magnesia. Long term - nephrotoxicity (80%), so shouldn’t be used in elderly w renal dysfunction/
Newer complexes have less nephrotoxic effects ex. Abelcet (lipid complex), amphotec (colloidal complex), amBisome (liposomal complex)
Nyastin
Polyene
Notes - Bind preformed ergosterol (cell membrane) & other sterols causing 1) membrane deformation 2) pore 3) leakage of K and Mg 4) metabolic derangement = cell lysis.
Used ONLY TOPICALLY bc TOO TOXIC for SYSTEMIC USE. Mainly for oral, oropharyngeal & perioral infections like albicans, thrush, stomatitis. Inactivated by gastric acid. Long therapy 10-14days required
S/E - disquetin (metallic bad taste), nausea, vomiting.
Ketoconazole, miconazole, clotrimazole
1st Gen Azoles (Imidazoles)
Notes - inhibit ergosterol synthesis by inhibiting CYP51 (converts lanosterol to ergosterol). Fungistatic @ low dose, fungicidal @ high dose.
SE - interfere with steroidogenesis, hepatotoxicity. DDI bc CYP inhibitor WARNING warfarin must lower dose of warfarin by 25%. Increased INR reported with miconazole
CAN BE USED WITH TERBINAFINE
ITRACONAZOLE CAN’T BE USED WITH KETOCONAZOLE. NO AZOLES TOGETHER
CAN’T BE USED WITH AMPHOTERICIN B
Oral and topical use requires acidity. No CSF penetration. Ketoconazole used for prostatic carcinomas @ high dose bc inhibits Testosterone synthesis. C/I in elderly on antacids/PPI bc increase pH = less absorption
Fluconazole, itraconazole
2nd Gen Azoles (Triazoles)
Notes - inhibit ergosterol synthesis by inhibiting CYP51 (converts lanosterol to ergosterol). Fungistatic @ low dose, fungicidal @ high dose.
CAN BE USED WITH TERBINAFINE
ITRACONAZOLE CAN’T BE USED WITH KETOCONAZOLE. NO AZOLES TOGETHER
CAN’T BE USED WITH AMPHOTERICIN B
SE - less effects on steroid synthesis and fewer S.E than 1st gen. Itraconazole only is a CYP inhibitor WARNING warfarin must lower dose of warfarin by 25% if concomitant
Oral & topical. Penetrates CSF. Better absorption & distribution. Used for fungal meningitis bc can cross BBB.
Voriconazole & Posaconazole
3rd gen Azole (broad spectrum triazoles)
Notes - inhibit ergosterol synthesis by inhibiting CYP51 (converts lanosterol to ergosterol). Fungistatic @ low dose, fungicidal @ high dose. USED FOR LIFE THREATENING ASPERGILLOSIS
CAN BE USED WITH TERBINAFINE
CAN’T BE USED WITH AMPHOTERICIN B
SE - interfere with steroidogenesis, hepatotoxicity. DDI bc CYP inhibitor WARNING warfarin must lower dose of warfarin by 25% if concomitant
Terbinafine, Naftifine, Amorolfine
Allylamine (reversible non- competitive inhibitor of squalene epoxidase)
Notes - Inhibit ergosterol synthesis. Toxic to fungal cell in 2 ways 1) increases concentration of squalene which is toxic bc it inhibits squalen epoxidase which converts squalene to squalene epoxide 2) Consequently ergosterol formation is decreased causing cell lysis.
CAN BE USED WITH AZOLES
Used topically and systemically for dermatophyte skin & nail infections. Inhibitor of CYP2D. SE- minor GI disturbances
Flucytosine
Fluorinated Pyrimidines (Active form is a pyrimidine analogue & antimetabolite that inhibits thymidylate synthase)
Notes - Pro drug. Block nucleic acid synthesis. Taken up by fungal machinery “permease” and converted to active form by fungal deaminase “cytosine deaminase” to FU which is broken down to active form FdUMP by DPD. Can inhibit DNA & RNA.
USED WITH AMPHOTERICIN B TO AVOID RESISTANCE BC IT MAKES A PORE TO GET IT INTO THE CELL
SE - minor GI disturbances. C/i in DPD deficiency bc flucytosine can’t be catabolized.
Caspofungin, micafungin, anidulafungin
Echinocandin
Notes - Reduce cell wall viability bc are non competitive inhibitors of glucan synthase that makes glucan for cell wall. SE - result from histamine release: flushed face, rash, fever, puritis
Rezafungin
Newest Echinocandin (March 2023)
Griseofulvin
Non-Polyene
Notes - Fungistatic. inhibit mitotic spindles & chromosome alignment by binding microtubules. It deposits in keratin precursor cells so new growth is also resistant to the fungus. Used for dermatophyte infections skin hair nails. Requires treatment for 6-9 months for fingernails, >1yr for toenails
SE - teratogenic, GI upset, photosensitivity. This is only used if other treatments are ineffective.
