Pharmacology Exam II

• amphotericin B
• fluconazole
• flucytosine
• itraconazole
• ketoconazole

• clotrimazole
• econazole
• griseofulvin
• miconazole
• nystatin

• systemic
• oral drugs
• topical drugs

• amphotericin B
• flucytosine
• azoles
• echinocandines

• plain
• cholesteryl sulfate complex
• lipid complex
• liposomal

• poorly absorbed from GI tract
• 90% protein bound
• widely distributed in all tissues but not CSF
• t1/2 = 15 days

• fungicidal or fungistatic depending on the organism
• binds ergosterol in the cell membrane and forms pores or channels
• disrupts membrane function and electrolytes (k+) leak from the cell resulting in cell death

it targets ergosterol not cholesterol

broad

• candidiasis
• endemic mycosis
• fungal pneumonia

• shake and bake syndrome (fever and chills, spasms)
• treated with NSAIDS
• reversable renal damage
• liver damage
• anemia

4 grams

• foscarnet
• ganciclovir
• tenofovir
• adefovir

flucytosine

• spectrum of action is narrow compared to Ampho B
• resistance can develop during therapy (not with ampho B)

• 90% oral absorption
• present in CSF because of poor protein binding
• renal excretion

• enters cell through cytosine-specific permease
• enzyme is absent in mammalian cells
• converted to 5-FU which is converted to 5-FdUMP
• this false nucleotide inhibits thymidylate synthetase inhibiting thymidylic acid synthesis (dna component)

• synergistic effects
• used in combo to lower doses of Ampho B so there is less toxicity

• cryptococcus neoformans
• candida
• chromoblastomycosis

• bone marrow toxicity resulting in anemia, leukopenia and thrombocytopenia
• GI irritation
• liver toxicity (less common)

• ketoconazole
• itraconazole
• fluconazole
• vorconazole

ketoconazole

ketoconazole

• fluconazole
• itraconazole

• broad spectrum antifungals
• effective for ampho B resistance

• inhibit ergosterol synthesis by inhibition of CYP450
• higher affinity for fungal CYP450 than for human CYP450

• minor GI irritation
• some effect on liver enzymes, rarely hepatitis
• some affinity for human CYP450 = drug interactions

• highest affinity for human CYP450
• typically used topically
• pregnancy category C

• inhibits conversion of lanosterol to ergosterol
• disrupts membrane function and increases permeability

• cyclosporine
• phenytoin - important not to mess with this (seizures)
• sucralfate
• terfenadine
• tolbutamide
• warfarin

• contraindicated
• ketoconazole antagonizes ampho B antifungal activity

• good oral absorption
• 90% protein bound (no CSF use)

• histoplasmosis
• blastomycosis
• onychomycosis

• can replace intrathecal ampho B
• not effective against aspergilli or filamentous fungi
• treatment failures in HIV pt.

fluconazole

• newest azole
• causes rash and elevated liver enzymes

• newest class of antifungals
• cyclic peptides linked to long chain fatty acids
• not orally absorbed
• short half life
• not active against cryptococcus neoformans

• caspofungin
• micafungin
• anidulafungin

• inhibit synthesis of beta-glucan via beta-glucan synthase which results in disruption of fungal cell wall
• fungistatic

• minor GI irritation
• elevated liver enzyme with cyclosporin
• anidulafungin may cause histamine release

• griseofulvin
• fungistatic

better with a fatty meal

binds keratin in keratin precursor cells and makes them resistant to fungal infections

• serum sickness
• hepatitis
• drug interactions by CYP induction
• potentiates the effect of alcohol

• itraconazole
• terbinafine

amphotericin B

• synthetic allylamine
• fungistatic

blocks squalene epoxidase in fungal cell wall leading to accumulation of sterol squalene which is toxic to the organism

• nystatin
• clotriazoles
• miconazoles

clotriazole and miconazole

azoles

flucytosine

nystatin and ampho B