ANTIFUNGAL DRUGS

Summary of antifungal drugs. Drugs for subcutaneous and systemic mycoses Voriconazole Posaconazole Micafungin Ketoconazole Itraconazole Flucytosine Fluconazole Caspofungin Anidulafungin Amphotericin B Drugs for cutaneous mycoses Terconazole Terbinafine Nystatin Miconazole Griseofulvin Econazole Clotrimazole Butoconazole (according to Lippincott´s Pharmacology, 2009)

Drugs for subcutaneous and systemic mycoses 1. Amphotericin B polyene ATB choice for life-threatening, systemic mycoses sometimes in combination with flucytosine – (structurally related to the cytostatic fluorouracil) binds to ergosterol in the plasma membranes - forms pores (channels) – electrolytes (particularly K) and small molecules leak from the cell - cell death. Against a wide range of fungi, incl. Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, many strains of Aspergillus. also protozoal infection, leishmaniasis. Administered by slow, i.v. infusion. Lipophilic – but no into CSF, cross placenta 3. Resistance: infrequent ( ergosterol content of the fungal membrane). The more dangerous intrathecal route. Low levels of the drug and metabolites appear in the urine over a long period; some are also eliminated via the bile. Dosage adjustment is not required in compromised renal or hepatic function.

Drugs for subcutaneous and systemic mycoses Amphotericin B - AE Fever and chills liposomes or microemulsion usually subside with repeated administration. premedication with a corticosteroid or an antipyretic helps to prevent it. anaphylaxis, convulsions Small test dose initially Renal impairment Adequate hydration is necessary. Hypotension A shock-like fall in BP with hypokalemia requiring K supplementation Anemia: Normochromic, normocytic anemia (by reversible suppression of erythrocyte production). Neurologic effects: Intrathecal administration - serious problems- convulsions, neuropathy.

Drugs for subcutaneous and systemic mycoses 2. Azole antimycotics Ketoconazole, itraconazole, fluconazole, voriconazole fungistatic - inhibit C-14 a-demethylase (P450) block demethylation of lanosterol to ergosterol - disruption of membrane structure and function Spectrum many fungi, incl. histoplasma, blastomyces, candida, coccidioides, but not aspergillus species. Only orally (it requires gastric acid for dissolution - absorbed through the gastric mucosa). Drugs that raise gastric pH (antacids, H2-histamine receptor blockers, proton-pump inhibitors) - impair absorption. Extensively bound to plasma proteins Rifampin (inducer of CYP450) can shorten the duration of action of azoles. Drugs that decrease gastric acidity -  absorption of ketoconazole. Ketoconazole and amphotericin B should not be used together (decrease in ergosterol reduces action of amphotericin B).

Azole antimycotics – AE Allergies dose-dependent GI disturbances (nausea, anorexia, vomiting) hepatotoxic - transient elevation of serum transaminases; hepatitis - rarely - immediate withdraw endocrine effects (gynecomastia, impotence, menstrual irregularities) via the block of androgen and adrenal (testosterone) synthesis - ketoconazol Teratogenic in animals - not administer in pregnancy Interactions Inhibition of CYP450 !!! - ketoconazol

Drugs for subcutaneous and systemic mycoses Ketoconasole Absorption dependent on pH in stomach Not into CNS Extensive metabolism in the liver – bile Enzyme inhibitor Itraconasole Broader spectrum - aspergillosis, and histoplasmosis Similar PK to ketoconazole Also P450 inhibitor but without endocrine effect Fluconazole Also for i.v – excellent CNS penetration - treatment of cryptococcal meningitis Lack of P450 interactions incl endocrine Kidney excretion Voriconazole, posaconazole New, broadest spectrum, resistant aspergilosis (vori), prevention of candidosis in immunocpmpromised - posa

3. Echinocandins Caspofungin, micafungin, anidulafungin A second-line antifungal for those who have failed or cannot tolerate amphotericin B or itraconazole. against aspergillus and candida species inhibit synthesis of the fungal cell wall inhibiting the synthesis of b(1,3)-o-glucan – cell death parenterally only Lipophilic - slowly metabolized (hydrolysis and N-acetylation) Adverse effects: fever, rash, nausea, phlebitis flushing due to histamine release The first member of the echinocandins Elimination by urinary and fecal routes. should not be coadministered with cyclosporine.

Drugs for cutaneous mycotic infection Terbinafine Drug of choice for dermatophytosis and, esp. onychomycoses E.g. Candida infection unuseful for treatment of systemic aspergillosis. Therapy is prolonged - usually about 3 months Fungicidal - inhibits fungal squalene epoxidase Only low affinity to human SE (cholesterol pathway) deposited in the skin, nails, and fat Orally active - More than 99 % bound to plasma proteins. Half-life ( 200 to 400 hours ) - reflects the slow release from these tissues. Accumulates in breast milk , should not be given to nursing mothers. Extensively metabolized deposited in the skin, nails, and fat Orally active (BAV about 40 % - first-pass metabolism). More than 99 % bound to plasma proteins. Half-life ( 200 to 400 hours ) - reflects the slow release from these tissues. Accumulates in breast milk  should not be given to nursing mothers. Extensively metabolized (but probably no significant risk of reduced clearance of other drugs); urinary excretion – in renal impairment or hepatic cirrhosis reduced clearance. Adverse effects: resolve upon drug discontinuation - GI disturbances (diarrhea, dyspepsia, and nausea), headache, rash are common. - Taste and visual disturbances. - Transient elevations in serum liver enzyme. - Rarely hepatotoxicity and neutropenia.

Terbinafine - AE GIT disturbances (taste, diarrhea, dyspepsia, and nausea), headache typical rash is common visual disturbances transient elevations in serum liver enzyme- rarely hepatotoxicity

Griseofulvin dermatophytic infections of the nails Largely replaced by terbinafine for the treatment. Fungistatic - requires treatment of 6 - 12 months in duration It accumulates in newly synthesized, keratin-containing tissue causes disruption of the mitotic spindle and inhibition of fungal mitosis. P.o. - absorption is enhanced by high-fat meals. induces hepatic CYP450 activity Number of interactions. e.g., oral anticoagulant drugs Blockade of alcohol dehydrogenase Patients should not drink alcoholic beverages during therapy griseofulvin potentiates the intoxicating effects of alcohol

Others Nystatin - polyene antibiotic. Its structure, chemistry, mechanism of action, and resistance resemble those of amphotericin. Only for topical treatment of candida infections because of systemic toxicity Not absorbed from GIT - Oral agent for the treatment of oral candidiasis. Excretion in the feces. Adverse effects: rare (nausea, vomiting).

Miconazole, clotrimazole - OTC, butoconazole, terconazole topical azole formulations AE - associated with contact dermatitis, - vulvar irritation, and edema miconazole is a potent inhibitor of warfarin metabolism (bleeding in warfarin-treated patients even when applied topically). Th. of seborrheic dermatitis