Antifungal Drugs

• Ketoconazole: (Nizoral)

  •  Less selective (than itraconazole (Sporanox) or fluconazole (Diflucan))for fungal cytochrome P450 enzymes. Accordingly:

    1.  ketoconazole (Nizoral)-- by inhibiting human cytochrome P450 inhibits adrenal and gonadal steroid hormone biosynthesis. Endocrine effects:

       •  gynecomastia

       •  infertility

       •  menstrual irregularities

    2. ketoconazole (Nizoral)-- altered metabolism of other drugs, increasing toxicity. Most important examples:

       •  increased cyclosporine levels

       •  increased arrhythmias associated with:

         • some nonsedating antihistamines

           • astemizole

           • terfenadine

  • Drugs influence ketoconazole (Nizoral) levels:

    • cimetidine (Tagamet)(by increasing gastric pH, interferes with ketoconazole absorption)

    • rifamycins (rifampin (Rimactane), rifabutin (Mycobutin)): increased azole hepatic metabolism

  • Clinical Use:ketoconazole (Nizoral)

    • Limited, due to endocrine side effects and drug-drug interactions and because of narrow therapeutic range. However may be used for low dose, effective treatment of:

      • mucocutaneous candidiasis

      • non-meningeal Coccidiodomycosis

• Itraconazole (Sporanox)

  • Oral administration

  • some interaction with hepatic microsomal P450 enzymes

    • no effect on steroid synthesis

    • Compared to ketoconazole (Nizoral), much less effect on metabolism of other drugs. Major drug-drug interaction: reduced itraconazole bioavailability when coadministered with rifamycins (rifampin (Rimactane), rifabutin (Mycobutin))

  • Most potent of azoles (efficacy may be limited by bioavailability)

  •  Poor penetration into cerebral spinal fluid

  • Clinical Use-Itraconazole (Sporanox): Agent of choice-

    • treatment of dermatophytes.

    • treatment of onychomycosis

    • only agent with substantial activity against Aspergillus species.

    • Preferred azole for treatment of diseases caused by dimorphic fungi:

      • Histoplasma

      • Blastomyces

      • Sporothrix

• Fluconazole (Diflucan)

  • Distinguishing feature: water solubility -- good cerebral spinal fluid penetration

  • excellent oral bioavailability

  • Limited drug-drug interactions; among azoles, least effect on cytochrome P450 hepatic microsomal enzyme system

  • Clinical Use-Fluconazole (Diflucan):

    • Wide therapeutic window

    • Azole of choice:

      • treatment and secondary prophylaxis -- cryptococcal meningitis

      • IV fluconazole -- equivalent amphotericin B (Fungizone, Amphotec)in treating candidemia in ICU patients (patients with normal white blood cell counts)

    • Effective in treating:

      • mucocutaneous candidiasis

      • coccidioidal disease -- high-dose fluconazole debuts in place of intrathecal amphotericin B

• Griseofulvin:

  • very insoluble; fungiostatic (derived from Penicillium)

  • Largely replaced in clinical use by itraconazole and terbinafine.

  • Single Clinical Use: systemic treatment of dermatophytosis

  • Mechanism of action-Griseofulvin:

    • binds to new skin keratin -- preventing news skin infection

    • long-term therapy may be required

  •  Adverse Effects-Griseofulvin:

    1. allergic syndrome (like serum sickness)

    2. hepatitis

    3. drug-drug interactions:

       • with warfarin

       • with phenobarbital

• Terbinafine: (Lamisil)

  • Oral formulation

  • karatophilic (like griseofulvin); fungicidal

  • Mechanism of Action:-- terbinafine inhibits fungal squalene epoxidase

    • squalene accumulates to toxic levels

  • Clinical Use: Terbinafine (Brethine)

    • Treatment of dermatophytoses

    • up to 90% cure rate for onychomycosis-- or effective than griseofulvin or itraconazole

  •  Adverse Effects:Terbinafine (Lamisil)

    • rare -- gastrointestinal upset, headache

    • no effect on cytochrome P450 microsomal enzyme metabolizing system

• Nystatin (Mycostatin)-- topical use

  • polyene macrolide -- like amphotericin B

  • Mechanism of Action: promotes membrane pore formation

  • topical use only -- due to systemic toxicity

  • Clinical Use-Nystatin (Mycostatin):

    • active against most Candida organisms

    • most often used for treating local candidal infections

      • oropharyngeal thrush

      • vaginal candidiasis

      • intertriginous (chaffed skin) candidal infections

• Common Topical Azoles:Clotrimazole (Mycelex),Miconazole (Monistat)

  • Clinical Uses-Topical Azoles:

    • vulvovaginal candidiasis

    • oral thrush (clotrimazole troches)

    • dermatophytic infections

      • tinea corporis

      • tinea pedis

      • tinea cruris

    • topical/shampoo ketoconazole:

      • seborrheic dermatitis

      • pityriasis versicolor

• Topical Allylamines (terbinafine (Lamisil), naftifine)

  • creams for tinea cruris;tinea corporis

Sheppard,D. and Lampiris, H.W., Antifungal Agents, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 780-786