Pharmacology of antifungal drugs (Fitz) Flashcards
Amphotericin B is this type of anti-fungal:
polyene
what is the MOA of amphotericin B?
penetrate cell membrane –> bind to ergosterol –> create pores –> Disrupt membrane integrity –> increase osmotic fragility
What is the therapyutic index of Amphotericin B? What are some adverse effects at onset of infusion? Later onset?
therapeutic index: poor ~1.5-2x
onset at infusion: Chills, fever, anemia, hypotension
later onset: nephrotoxicity –> direct damage to distal tubule membrane; Na, K, mg wasting, hypokalemia; Decreased GFR (arteriole constriction)
Amphotericin B aggravates the nephrotoxicity of other drugs, particularly these types of pts:
transplant, allograft pts: cyclosporine, sirolimus, tacrolimus
HIV pts: Foscarnet, pentamidine
Serious infx: Gram -, MRSA (Aminoglycosides, vancomycin)
What type of anti fungal drug is Fluconazole?
1st generation Triazole
what is the MOA of Azoles?
create deficit of ergosterol –> disrupt sterol content (create Lanosterol surplus, inhibit formation of ergosterol)
what are indications for Fluconazole?
Narrow spectrum
Candida albicans (candidemia, local candidiasis)
Cryptococcus (meningitis, with AMP-B)
what are limitations of Fluconazole?
NO activity vs Aspergillus
2nd line vs most true pathogens
What is the clearance of Fluconazole?
renal (75%)
what is the bioavailability and absorption of Itraconazole?
Poor bioavailability (50%) Poor solubility (requires acid)
what type of CSF access does Itraconazole have? Does it have any interaction with CYP450?
poor CSF access
Strong CYP450 inhibitor
This triazole is the drug of choice/recommended for Aspergillus spp
Voriconazole
This triazole is the drug of choice/recommended for histoplasmosis, coccidioides, and blastomycoses:
Itraconazole
this triazole is resistant to “other” candida and can be used for cryptococcus:
fluconzaole
list some fungal resistance mechanisms to azoles:
- mutation of lanosterol-14a-demethylase
- overexpression of lanosterol-14a-demethylase
- energy-dependent efflux systems
- changes in sterol and/or phospholipid composition of fungal cell membrane (decreased permeability)
Caspofungin is what type of anti-fungal?
Echinocandin
what is the MOA of Caspofungin
Inhibits B(1,3) glucan synthase
Describe the pharmacokinetics of Caspofungin:
- Well-tolerated
- Hepatic metabolism
- Few drug interactins
what are some therapeutic indications for Caspofungin?
Opportunistic infx (serious) –> invasive candidiasis, candidemia; Invasive aspergillosis
What are some therapeutic limitations of Echinocandins (Caspofungin)? i.e., what are they not effective against?
Histoplasmosis
Coccidioidomycosis
Fusarium spp
What are therapeutic indications of triazoles for opportunistic infx? Pathogenic infx?
opportunistic –> aspergillus, candida, rhizopus, cryptococcus
pathogenic –> histoplasma, coccidioides, blastomyces, paracoccidiodies
what are some indications for Itraconazole?
Broad spectrum –> covers candida, some activity vs aspergillus
Front line/recommended for histoplasmosis, coccidioides, blastomycoses, true pathogenic infx
what is a major adverse effect of Ketoconazole?
Gynecomastia and decreased libido
inhibits human adrenal and gonadal steroid synthesis
what are some “pros” for absorption and distribution of Voriconazole and Fluconazole?
both are readily absorbed (>90% bioavailability) with excellent distribution including CSF
What are some “cons” for absorption and distribution of Itraconazole?
Like ketoconazole; it requires gastric acidity to dissolve. Poor CSF penetration
these triazoles are strong inhibitors of hepatic CYP450 and enhance renal toxicity:
voriconazole and itraconazole
what are common and rare side effects of vori/flucon/itraconazole?
avoid all triazoles in pregnancy
all triazoles can damage liver
genetics alter voriconazole clearance
voriconazole disturbs vision
This is the drug of choice for Mucormycosis (zygomycosis)
Amphotericin B
that Joplin slide
this is the drug of choice for cryptococcal meningitis
Amphotericin B
lipid formulations and in combo with 5-FC
