How is widespread tinea treated?
terbinafine, itraconazole, fluconazole, griseofulvin
How is localized tinea treated?
-azoles, terbinafine, naftifine, ciclopirox
What are the treatment options for onychomycosis?
PO: terbinafine, griseofulvin, itra, fluconazole
Topical: Ciclopirox, amorolfine
T or F. Topical drug therapy is largely devoid of significant systemic toxicity
T. if used as indicated.
Recent FDA ruling on ketoconazole
The FDA is moving to restrict further use of this agent only to topical use, because of issues of toxicity including:
-adrenal dysfunction, via this azole's ability to interupt intermediary synthetic pathways of steroid synthesis, leading to an inability to synthesize adequate cortisol.
Whereas the remaining azoles do not have this aspect to their pharmacology, you will notice a recurring theme in regards to the other 2 issues listed here. The first is hepatoxicity/dysfunction, and the second is inhibition of CYP activity, potentially leading to elevated serum levels of concurrent drugs.
AEs of Itraconazole?
-negative inotropic effect (heart failure, ventricular dysfunction)-BBW
-Category C teratogen (can be present in breast milk as well)
Common toxicities of fluconazole, posaconazole, and voriconazole?
-contraindicated in pregnancy
Unique AEs of voriconazole?
-visual disturbances (optic neuritis-photophobia, color changes)
-photosensitizes skin (SCC and melanoma reported)
______ must be administered with a full meal or acidic carbonated drunk for adequate bioavailability
How are the azoles metabolized?
Most undergo hepatic metabolism but Fluconazole is eliminated renally (dose adjustment necessary)
Which AZOLEs have good CNS penetration?
-**Fluconazole** and Voriconazole (via P-gp interactions)
T or F. Griseofluvin can be given topically
F. It is unable to penetrate skin
How is Griseo metabolized and eliminated?
It undergoes hepatic metabolism and is eliminated in a mixture of renalhepatic/perspiration
AEs of Griseo?
-disulfram-like effect (like metronidazole and cefotetan and some PO anti-diabetic agents)
-Interferes with porphyrin metabolism
Griseofluvin is a CYP inducer. What are some drugs affected by this?
-coumarin and warfarin are less effective
-oral contraceptives are less effective
-cyclosporine is less effective
-ethanol effects are increased (tachycardia, diaphoresis, flushing)
Common AE of Griseo?
Note: There is an issue of cross-sensitivity of griseofluvin with penicillin, cephalosporin, or carbapenem hypersensitivity.
How does Griseofluvin work?
.Griseofulvin is fungistatic, however the exact mechanism by which it inhibits the growth of dermatophytes is not clear. It is thought to inhibit fungal cell mitosis and nuclear acid synthesis. It also binds to and interferes with the function of spindle and cytoplasmic microtubules by binding to alpha and beta tubulin. It binds to keratin in human cells, then once it reaches the fungal site of action, it binds to fungal microtubes thus altering the fungal process of mitosis.
How does Terbinafine work?
terbinafine inhibits ergosterol synthesis by inhibiting the fungal squalene monooxygenase (squalene 2,3-epoxidase), an enzyme that is part of the fungal cell wall synthesis pathway
Metabolism of Terbinafine?
Hepatic metabolism with renal elimination
AEs of Terbinafine?
-transient lymphopenia and neutropenia with oral drug (avoid in immunosuppressed)
-category B preg
monitor CBC and LFTs
How does Naftifine work?
selectively inhibits enzyme squalene 2,3-epoxidase
At higher doses, this drug is also locally bactericidal and has anti-inflammatory properties via inhibition of prostaglandins, leukotrienes, and histamine
Notes about Naftifine
topical agent (no significant systemic drug interactions)
hepatic metab/renal elim
-cat B drug
How does Ciclopirox work?
Unlike antifungals such as itraconazole and terbinafine, which affect sterol synthesis, ciclopirox is thought to act through the chelation of polyvalent metal cations, such as Fe3+ and Al3+. These cations inhibit many enzymes, including cytochromes, thus disrupting cellular activities such as mitochondrial electron transport processes and energy production.
Ciclopirox also appears to modify the plasma membrane of fungi, resulting in the disorganization of internal structures. The anti-inflammatory action of ciclopirox is most likely due to inhibition of 5-lipoxygenase and cyclooxygenase. Ciclopirox may exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.
Notes about Ciclopirox (Penlac) and Amorolfine (Loceryl)
Topical only; limited absorption
How does Amorolfine work?
Inhibits ergosterol synthesis