Antifungal and antiprotozoan drugs

Question 1

Amphotericin B

Answer 1

Mechanism: Polyene molecule- binds ergosterol; forms membrane pores -> electrolytes leak out

Clinical use: serious systemic mycoses (w or w/out flucytosine for crpyto meningitis); Intrathecally for fungal meningitis. Last resort for protozoan infections. *Supplement K+ and Mg2+ bc altered renal tubule permeability

Toxicity: fever/chills, hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis
*Hydration -> decrease nephrotoxicity, Liposomal amphotericin -> decrease toxicity

Question 2

Nystatin

Answer 2

Polyene, Same mechanism as amphotericin B- binds ergosterol and creates membrane pore

Clinical use: topical only (too toxic for systemic use), “swish and swallow” for oral candidiasis; topical for diaper rash or vaginal candidiasis

Question 3

Flucytosine

Answer 3

Mechanism: Inhibitis DNA and RNA synthesis by conversion to 5-FU by cytosine deaminase

Use: systemic fungal infections - especially cryptococcus meningitis in combo with amphotericin B and candida infections

Toxicity: bone marrow suppression

Question 4

Azoles

Answer 4

Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole

Mechanism: inhibit fungal sterol (ergosterol) synthesis through inhibition of P450 enzyme that converts lanosterol –> ergosterol

Clinical use: local and less serious systemic mycoses
Fluconazole - chronic suppression of cryptococcal meningitis in AIDS patients and candida infections (all types)
Itraconazole for Blastomyces, Coccidioides, Histoplasma

Side effects: liver dysfxn (P450 inhibition), inhibition of testosterone synthesis (gynecomastia esp with ketoconazole)

Question 5

Terbinafine

Answer 5

Mechanism: inhibits fungal enzyme squalene epoxidase

Clinical use: dermatophytoses (especially onychomycosis)

Toxicity: GI upset, HA, hepatotoxicity, taste distrubance

Question 6

Echinocandins

Answer 6

Anidulafungin, caspofungin, micafungin

Mechanism: inhibit cell wall synthesis by inhibiting beta-glucan synthesis

Clinical use: Invasive aspergillosis, Candida

Toxicity: GI upset, flushing (histamine release)

Question 7

Griseofulvin

Answer 7

Mechanism: interferes with MT fxn; disrupts mitosis. Deposits in keratin-containing tissues (eg nails)

Clinical use: oral treatment of superficial infections, inhibits growth of dermatophytes (tinea, ringworm)

Toxicity: Teratogenic, carcinogenic, confusion, HA, induces cytochrome P450 and warfarin metabolism