Chemotherapeutic Drugs: Antifungal Agents Flashcards
- Describe the major principles for anti fungal therapy.
target something that is contained in fungal but not human cells to inhibit growth (ergosterol, chitin, B-glucan, and mannoproteins)
tx. for established invasive fungal infections has lagged behind antibacterials, which becomes problematic with growing number of immunocompromised
2-7. Explain the mechanisms of action, spectrum of action and pharmokinetics for amphotericin B
cidal activity from binding of drug to ergosterol and causing a hole in the membrane altering permeability to K+ and Mg++; AmB is oxidized resulting in formation of free radicals
most broad spectrum anti fungal (most except Candida lusitaniae and Aspergillus terries)
insolulable in water, available only in IV, once daily, liposomal has best CNS penetration, no dose adjustment; lipid formulations improve therapeutic index and reduce nephrotoxicity
2-7. Explain side effects/ drug interactions for amphotericin B.
toxicity is dose limiting, lipid formulations less toxic, less potent: nephrotoxic 80% (**distal tubular acidosis), infusion rigor/fever 50%, normochromic-normocytic anemia (suppression of erythropoectic synthesis)
nephrotoxicity due to decreased renal blood flow, distal tubular ischemia and loss of H, K and Mg (dose dependent) admin IV saline
infusion related toxicity: TNFa and interluekin-1 cause fever, chills, NV, myalgias and bronchospasm (rate dependent)
2-7. Explain the major clinical indications for amphotericin B
first line for cryptococcal meningitis, severe endemic fungal infection and initial therapy for zygomycosis (mucor)
2-7. Explain the mechanisms of action, spectrum of action and pharmokinetics for fluconazole.
azoles inhibit the synthesis of ergosterol by blocking demethylation of lanosterol (static for candida and cidal for aspergilus)
action against Candida except C. glabrata and C. krusei; crypto, and endemic fungi
available in IV, oral; good absorption with renal elimination, adjust by renal insufficiency, CYP450 inhibitor, may cause endocrine side effects (also terotogenicity)
2-7. Explain the side effects/ drug interactions, and major clinical indications for fluconazole.
toxicities include: teratogenicity (most specific for fungal p450), rare hepatotoxicity, QT prolongation (prolonged high doses- alopecia and dry lips), rare nausea
1st line for mucosal Candidiasis and step down 1st line for Candida cystitis treatment (not glabrata or krusei) 1st line Coccy meningitis invasive candidiasis option for endemic infection NOT aspergillus
rare resistance esp with HIV/AIDS by intrinsic and developed resistance (alteration of target enzymes and efflux from cell)
2-7. Explain the mechanisms of action, spectrum of action, and pharmokinetics for itraconazole.
triazole: inhibits ergosterol production
unique spectrum- Sporothrix shenckii, Aspergillus, Penicillium and pheohyphomycetes
IV and oral- liquid and capsule (requires acid and food); poor CNS and urine penetration, hepatic elimination, ** therapeutic drug monitoring is important, IV only with normal GFR due to accumulation of carrier
formulation with cyclodextran (ring of glucose) enables solubilziation and delivery to the lipid interface of GI lumen, increases absorption and increased oral bioavailability
2-7. Explain the side effects/ drug interactions, and major clinical indications for itraconazole.
toxicity: more GI than fluconazole, NV, some hepatotoxicity, QT prolongation and teratogenicity
1st line against dermatophytes, Sporothrix and simple Aspergillus infection, effective against endemics and t of resistant candidiasis
2-7. Explain the mechanisms of action, spectrum of action, and pharmokinetics for voriconazole.
inhibits ergosterol synthesis
action against all fluconazole plus C. glabrata and C. krusei and all aspergillus spp. Trichosproin beigilii, Fusarium, P boydii and dimorphic fungi (most except zygomycetes), more potent against resistant C. albicans
good absorption, active in CNS, no urine; requires twice daily dosing (binds to protein) and metabolism is extremely variable with CYP19 and drug interactions with CYP450 (TDM)
2-7. Explain the side effects/ drug interactions, and major clinical indications for voriconazole.
toxicity: common visual photopsia, more hepatotoxicity, rare hallucinations, photosensitivity of skin, bone toxicity, teratogenic, QT prolongation
1st line invasive aspergillosis
option for endemics and Candida (2nd)
2-7. Explain the mechanisms of action, spectrum of action, and pharmokinetics for flucytosine.
5-FC is a pyridine analogue, inhibits DNA and protein synthesis in fungal cells, competes at FUMP (gut does contain enzyme for conversion = toxicity)
fungistic against yeasts (mostly just Candida and Crypto), selects for resistance, synergistic with AMB against Candida and Crypto
water soluble, only oral, great absorption, distribution in urine and CNS (all renal excretion); VERY short half-life, adjust with renal function, primary metabolite is quite toxic
2-7. Explain the side effects/ drug interactions, and major clinical indications for flucytosine.
life threatening toxicity with high doses concentrations, bone marrow suppression and hepatitis (associated with ampB with nephrotoxin)
1st line combo with amp B for induction Crypto meningitis, used alone except for Candida TUI
2-7. Explain the mechanisms of action, spectrum of action, and pharmokinetics for terbinafine.
allylamines inhibit ergosterol synthesis at the level of squalene epoxidase
fungicidal for dermatophytes, Aspergillus, dimorphic fungi and PCP
very highly non saturable protein binding limits utility of compound, concentrates in stratum corneum
2-7. Explain the side effects/ drug interactions, and major clinical indications for terbinafine..
essentially no toxicity
indicated for skin and nail dermatophyte infections
2-7. Explain the mechanisms of action, spectrum of action, and pharmokinetics for micafungin.
echinocandin: (amphophilic) cidal for candida and static for aspergillus
inhibit 1,3, B-D glucan synthase to prevent glucan polymer cell wall formation leading to osmotic instability, long elimination half life
fugicidal against Candida, active against C. glabrata dn C. krusei
Fungistatic against aspergillus
no Crypto or endemic fungi activity
