Anti-fungal Drugs - Katzung

Pharmacology Antifungals (book) 22 January 08 ANTIFUNGAL AGENTS

Amphotericin B binds with (1) lipids—ergosterol along the double bond-rich side and (2) water molecules along the hydroxyl-rich side Amphipathic characteristic facilitates pore formation Pore allows leakage of intracellular ions and macromolecules  cell death 

FOUR GENERAL TYPES OF MYCOTIC INFECTIONS: A. Cutaneous B. Subcutaneous C. Superficial D. Systemic 1. May be life-threatening 2. Often occur in immunocompromised patients

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FOUR MAJOR GROUPS OF ANTIFUNGAL AGENTS BASED ON CHEMICAL STRUCTURE: (from the lecture) A. Polyenes 1. Amphotericin B 2. Nystatin B. Azoles 1. Imidazole  Ketoconazole,  Miconazole  Clotrimazole 2. Triazole  Itraconazole  Fluconazole  Voriconazole C. Flucytosine D. Griseofulvin Molecular orientation in an amphotericin Bcholesterol pore. The dotted lines between the hydrocarbon chains of phospholipids represent short-range London-van der Waals forces. The dashed lines represent hydrogen bonds formed between amphotericin B and cholesterol molecules.

THREE GROUPS ACCORDING TO USE: (from the book) A. Systemic antifungal drugs for systemic infections 1. Amphotericin B 2. Flucytosine 3. Azoles 4. Echinocandins B. Systemic antifungal drugs for mucocutaneous infections 1. Griseofulvin 2. Terbinafine C. Topical antifungal therapy 1. Nystatin

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POLYENES Includes amphotericin B and nystatin Bind to sterols and cell membrane lining  creates holes  increase cell permeability Allows K+ and Mg++ to leak out

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ANTIFUNGAL ACTIVITY o Activity against:  Yeasts − Candida albicans − Cryptococcus neoformans  Organisms causing endemic mycoses − Histoplasma capsulatum − Blastomycoses dermatitidis − Coccidioides immitis  Pathogenic molds − Aspergillus fumigatus − Aspergillus mucor o Amphotericin B-resistant organisms:  Candida lisitaniae  Pseudallescheria boydii

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CLINICAL USE o Used as initial induction regimen for serious fungal reaction o Used as empiric therapy for selected pts (e.g. febrile Ca pts w/ neutropenia on broad-spec antibiotics) o Used as treatment of systemic fungal disease (IV) o Used as intrathecal therapy for fungal meningitis o Used as topical drops for mycotic corneal ulcers & keratitis o Used as adjunctive local injection for fungal arthritis

Amphotericin B Amphotericin A is not in clinical use An amphoteric polyene (containing double bonds) macrolide (containing a large lactone ring of 12≥ atoms) Insoluble in H2O therefore prepared as colloidal suspension PHARMACOKINETICS o Poorly absorbed in the GIT o Mostly metabolized in the kidney o Serum t1/2: approx. 15 days o No dose adjustment needed for hepatic & renal impairment and dialysis MOA o Binds to ergosterol and alters permeability of the cell by forming amphotericin B-associated pores in the cell membrane o Amphipathic characteristic

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Toxicity: May occur due to its ability to bind to human membrane sterols Resistance may occur due to:  Impaired ergosterol binding either by : − Decrease in the membrane concentration of ergosterol − Sterol target molecule modification to reduce its affinity for the drug

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Pharmacology – Antifungal Agents from the book and my notes o E.

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Used as bladder irrigation for candidiasis

ADVERSE EFFECTS o Two categories of amphotericin B toxicity  Immediate reactions (related to drug infusion)  Slow reaction o “shake and bake”: chills, fever, headache, anorexia, anaphylaxis, malaise, nausea, hypotension, tachycardia, K+ & Mg++ losses o Renal toxicity o Neurotoxicity

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ADVERSE EFFECTS o Relatively non-toxic o Minor GI upset o Abnormalities in liver enzymes; clinical hepatitis (rare)

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DRUG INTERACTIONS o A lot!  cyP450

Nystatin

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Too toxic for IV administration  TOPICAL USE ONLY Not absorbed significantly in the skin, mucous membranes / GIT  little toxicity Unpleasant taste Active vs candida species Common indications: oropharyngeal thrush, vaginal candidiasis, intertriginous candidal infections FLUCYTOSINE PHARMACOKINETICS o a.k.a. 5-FC o H2O-soluble pyrimidine analog o Removed by hemodialysis MOA o Taken up by fungal cells  interferes w/ DNA (by FdUMP) and RNA (by FUTP) synthesis o In vitro & in vivo synergy w/ amphotericin B (enhances 5-FC penetration) o In vitro synergy w/ azole drugs (unknown mechanism) o Resistance may occur due to altered 5-FC metabolism in 5-FC monotherapy CLINICAL USE o Restricted to Cryptococcus neoformans, some candida sp., & dematiaceous molds (causes chromoblastomycosis) o Not used as single agent  avoid 2˚ resistance o 5-FC + amphotericin B = cryptococcal meninigitis o 5-FC + itraconazole = chromoblastomycosis ADVERSE EFFECTS o N & V, anorexia o Agranulocytosis (decreased WBC) o Confusion, hallucination, headache, sedation o BM toxicity w/ anemia, leukemia, & thrombocytopenia (most common) o Increase in liver transaminases (less frequent) o Enterocolitis o Renal toxicity(Increase in kidney BUN and creatinine) more likely in AIDS pts & those w/ renal insufficiency AZOLES PHARMACOLOGY o Imidazole: ketoconazole, miconazole, clotrimazole o Triazole: itraconazole, fluconazole, voriconazole MOA o Inhibition of fungal cyP450  reduction of ergosterol synthesis  Increase in cell permeability  inhibition of fungal cell growth o Specificity: Imidazole < triazole  higher incidence of s.e. CLINICAL USE o Candida sp. o Cryptococcus neoformans o Endemic mycoses  Blastomycosis

 Coccidioidomycosis  Histoplasmosis Dermatophytes Aspergillus infections (itraconazole & voriconazole) Pseudallescheria boydii (ampho-resistant)

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Ketoconazole 1st oral azole With dermatologic use Inhibition of fungal cyP450  reduction of ergosterol synthesis  Increase in cell permeability  inhibition of fungal cell growth S.E.: Rash (topical), anaphylaxis, N & V, liver cirrhosis, gynecomastia, uterine bleeding, loss of libido, impotence, oligospermia, hair loss, acute hypoaldosteronism, renal hypofunction Fluconazole High degree of H2O solubility Good CSF penetration High bioavailability Widest therapeutic index Oral & IV Inhibition of fungal cyP450  reduction of ergosterol synthesis  Increase in cell permeability  inhibition of fungal cell growth DOC & 2˚ prophylaxis: Cryptococcal meningitis Prophylaxis: fungal disease in BM transplant & AIDS pts Tx: mucocutaneous candidiasis No activity vs. aspergillus / filamentous fungi S.E.: Headache, N & V, abdominal pain, diarrhea, increase AST in Px w/ cryptococcal meningitis & AIDS Miconazole Inhibit uptake of components essential for cell reproduction & growth as well as cell wall structures, thus promoting cell death of fungi S.E.: Vulvovaginal burning when used as ointment, cream and vaginal suppository, itching, irritation, maceration, allergic contact dermatitis Clotrimazole Altering fungal cell membrane permeability  Permeating loss of P cmpds, K & other essential intracellular constituents  loss of ability to replicate Abnormal liver function tests, stinging, erythema, edema, cystitis, urethritis, vaginal soreness during intercourse

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Voriconazole Newest DOC: Aspergillosis S.E.: rash, elevated hepatic enzymes, visual disturbances

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Itraconazole Oral & IV Drug interaction: reduced bioavailability if taken w/ rifamycins DOC: dismorphic fungi histoplasma

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GRISEOFULVIN Disrupts cell division  inhibited fungal mitosis (reproduction) Deposits in keratin precursor cells & has special affinity for diseased tissue. It is tightly bound to new keratin of skin, hair, & nails, w/c becomes highly resistant to fungal invasion  must be administered for 2 – 6 wks Absorption increased by fatty foods S.E.: Rash, urticaria, headache, N & V & anorexia, leucopenia, nephrotoxicity, hepatotoxicity, overgrowth of nonsusceptible organisms (Candida)