Glossary of ID 6.4

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Topical Antifungal Agents
Many available, esp. OTC
Choice depends on fungus and location (creams/solutions better suited for fissured/wet places and powders are good prophylactic agents)
Vaginal Antifungal Agents
Most appeciated: least messy and shortest application time.
1 150mg fluconazole (for yeast infections)
Treating Oral Candidiasis (Thrush)
Clotrimazole > Nystatin
Historial Use
Active against dermatophytes but NOT AGAINST CANDIDA
Oral, SYSTEMIC therapy for cutaneous infections
Griseofulvin (historical interest) - DONT USE IT
Terbinafin (Lamisil)
Mechanisms of Antifungal Medication
Most work at plasma membrane (ergosterol synthesis, similar to our own cholesterol synthesis so issues w/toxicity)
Newer generations target beta-glucan (penicillins for fungi)
Nail and dermatophyte infections
Broad spectrum, oral systemic therapy
Lipophilic - binds to stratum corneum and stays for a long time
Enables you to bolus drug (on 1 week, off 3 weeks for 3/4 cycles)
Amphotericin B
AMPHI - has acid/base
PolyENE (multiple double bonds) - light sensitive and yellow color
Amphotericin B
Lipophilic, mix w/biosalt (deoxycholate) and forms micelles
If mix w/salt suspension, clumps
Therefore mix in D5W (dextrose/water - NO salt) ONLY
Amphotericin B
(mechanism of action)
Inserts into PM
Binds to ergosterol
Like staves on a barrel, forms a PORE
Problem, also binds to cholesterol (will see lysis of RBCs, etc)
Amphotericin B
(pharmacology in body)
In blood stream, disassociates from deoxycholate and binds LDL - plasma protein(contains tons of cholesterol)
Binds to densely vascular tissue (liver, spleen, kidneys, lungs) - which then serves as a resevoir as plasma levels fall (why amphotericin has such a long 1/2 life - 2 weeks!)
Why is Amphotericin especially nephrotoxic?
Renal tubular cells have receptors for LDL (which binds amphotericin B)
When treating, avoid drugs that cause dehydration, etc
You need to especially monitor their salt levels - they'll drop(K, Mg, HCO3)
Amphotericin B
(side effects)
Acute: "shake and bake" (due to PGE2, TNF, IL-1 - treat with NSAID? NO! AmphiB knocks out efferent and NSAIDS knock out afferent - lose renal function!)
Chronic: normochromic/normocytic anemia
Lipid-associated Amphotericin B Preparations
Fat-containing amphotericin B more efficiently target areas of infection
When they disassociat, they're picked up by HDL (vs. LDL) and therefore, have significantly less impact on Kidneys
One's available: liposomal Amphitericin B (AmBisome); Amphotericin B lipid comoplex (ABLC)
Inhibit ergosterol synthesis
Types: imidazoles; triazoles
Imidazoles vs. Triazoles
Both Azoles (block ergosterol synthesis and fungistatic)
However, triazoles have greater affinity to funal CYP450 enzymes
of Imidazole class
Oral dose, requires gastric acid
Toxicity limits its utility (hepatic problems)
Little utility but great for treatment of patients with prostate cancer
Good bioavailability
Excreted in urine (good for UTIs)
CSF entry
Minimal toxicity
Unpredictable pharmacokinetics, requires gastric acid (instituted IV alternative, but rarely used) but broad spectrum of activity
Azole Pharmacology
All insoluble in water, therefore if IV, must use Beta-cyclodextrin vehicle, but accumulates in patients with renal insufficiency and possibly carcinogenic!
Daughter of fluconazole with greater specificity (can get into CNS)
PO and IV preparation
Issue: metabolized by several cytochrome enzymes (drug interactions common); abnormal electroretinograms (LSD-like trip)
Which azoles require gastric acid?
Ketoconazole and Itraconazole
Azole to treat fungal UTI?
Azole to treat fungal CNS infection?
Fluconazole > voriconazole > itraconazole
Contraindication to Azole administration?
These guys are heavily metabolized by liver, therefore numerous drug interactions
"Daughter of itraconazole"
Adv? Advantage against zygomyces
Interferes with DNA synthesis
Good levels at CNS/urine
Toxicity? Bacteria can metabolize to 5-FU (chemotherapeutic agent) which can reach toxic levels if poor clearance mechanisms
What is the clinical advantage of 5-FC?
Used w/AmB to treat cryptococcal meningitis
Large, complicated structures
Fungicidal, act on cell wall
No drug interactions (hydroxylated vs. going through CYP450 system)

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