Anti-fungal Pharmacology Elly Nurus Sakinah Lab Farmakologi FKUJ 2017

What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001

7 POLYENE: Amphotericin B  Polyene berikatan dengan ergosterol membran  merubah permeabilitas membran sel  PREPARAT:  Injeksi:  Conventional formulation: Fungizone (50 mg)  Lipid formulation: Abelcet (100 mg/20 ml susp); AmBisome (50 mg); Amphotec (50,100 mg)  Topical: cream, lotion, ointment  Fungisidal/Fungistatik  tergantung dosis  RESISTENSI:  Me↓ konsentrasi membran thd ergosterol  Mutasi target sterol

8  INDIKASI:  Systemic fungal infection : candida, cryptococcus, histoplasmosis  Tx akut px immunosuppressed  Tx lokal: ulcus kornea & keratitis; artritis; candiduria  Krn toksik  penggunaan klinik ↓  Infusion related : nyeri, demam, spasme otot, shock like (↓TD)  premedikasi dg antihistamin, antipiretik, steroid  Nefrotoksik  hipo K, hipo Mg, anemia  dose reduction (kombinasi dengan flucytocine); liposomal formulation  me↓ ikatan obat dengan sel ginjal  Neurotoksik : kejang POLYENE: Amphotericin B...(2)

9 FLUCYTOSINE...(1)  Setelah penetrasi ke sel jamur  dirubah mnjd fluorouracil (5-FU) oleh enzim cytosine deaminase  interaksi dg RNA jamur dan meng3 sintesis protein  Fungistatik  RESISTENSI:  RESISTENSI: mutasi enzim cytosine deaminase/permease  FARMAKOKINETIK:  FARMAKOKINETIK: abs cepat per oral, distr luas (CNS,mata,tract urinary), eliminasi lewat urine, tidak perlu penyesuiaian dosis pada px dg gangguan ginjal

10  INDIKASI:  Candidiasis sistemik, cryptococcus  Spektrum antifungal sempit  Kombinasi dg amphotericin B atau dg triazole  uptake flucytosine dr plasma membran me ↑  TOKSISITAS:  TOKSISITAS: supresi bone marrow (leukopenia, thrombositopenia), disfgs hepar  KONTRA INDIKASI:  KONTRA INDIKASI: Bumil  PREPARAT:  PREPARAT: Ancobon (cap 250, 500mg; 4x/hr) FLUCYTOSINE...(2)

11  Imidazole: Ketoconazole, Clotrimazole, Miconazole,  Triazole: Itraconazole (Posaconazole), Fluconazole (Ravuconazole), Voriconazole, Terconazole  PK : oral = iv; absorbs oral Fluconazole, Voriconazole > dari yang lainnya  Distribusi : luas (kec. Fluconazole rendah di CNS  Fungistatik > Fungisid  Relatif non toksik; g3 GIT, inhibitor enzim Cyt P450 AZOLE

Azoles - Mechanism In fungi, the cytochrome P450- enzyme lanosterol 14-  demethylase is responsible for the conversion of lanosterol to ergosterol Azoles bind to lanosterol 14  - demethylase inhibiting the production of ergosterol Some cross-reactivity is seen with mammalian cytochrome p450 enzymes Drug Interactions (rifampicin) Impairment of steroidneogenesis (ketoconazole, itraconazole)

Ketokonazole  IT sempit, E/S lebih banyak  FARMAKOKINETIK  Abs pd pH ↓: jangan u/ px achlorhydria atau px yg m’konsumsi bicarbonate, antasid, H2- blocker, PPI  Distr CSF & UTI ↓  Tidak ada sediaan Parenteral  Efektif untuk dermatofitosis  E/S : Hepatoxicity (2-8%), increase in transaminases, hepatitis

Ketoconazole - Drug Interactions Potent inhibitor of cytochrome P450 3A4 Rifampin and phenytoin decrease ketoconazole levels Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophylline levels Many of these drug interactions are severe Dose related inhibition of CYP P450 responsible for testosterone synthesis Gynecomastia, impotence (azoospermia)

15  Per oral & iv  IT luas  Abs tidak tgt pH lambung  Terdifusi scr bebas: CSF sputum, urine & saliva  Indikasi: DOC candidiasis orofaringeal,candidiasis vaginal & cryptococcal meningitis Tidak efektif u/ aspergillosis  Resistensi ↑ (tu candidiasis) FLUCONAZOLE

16  Broad spectrum  Absorbsi oral ∞ pH lambung (=ketokonazole)  Bioavailability per oral unpredictable  iv  Distr CSF, UTI & saliva ↓  Aktivitas ↑ : aspergillosis, blastomycosis, histoplasmosis, bagus untuk Tx onychomycosis  Teratogenic (kategori C)  ES: Hepatotoksik ITRACONAZOLE

17 ECHINOCANDIN...(1)  Glucan synthase inhibitor  menghambat sintesis dinding sel jamur  PREPARAT:  PREPARAT: Caspofungin (Cancidas: 50, 70 mg), Anidulafungin, Micafungin  iv 1x/hr  Fungistatic (Aspergillus spp) Fungicidal (Candida spp)  FARMAKOKINETIK:  FARMAKOKINETIK: ik prot ↑ ; distr pd CSF <

Systemic drugs for superficial fungal infection Griseofulvine Terbinafine

19 GRISEOFULVIN...(1)  MEK. KERJA: Ik tubulin & mikrotubulin prot  g3 mitosis: Ox dihimpun dlm sel pembentuk keratin  Ik kuat dg keratin sel baru  sel baru resisten jamur  keratin berjamur lepas ≈ sel baru Penting: tx tuntas  FARMAKOKINETIK:  FARMAKOKINETIK: abs ↑ (makanan b’lemak); enzim inducer (kontrasepsi oral low-estrogen)

20 GRISEOFULVIN...(2)  PREPARAT:  PREPARAT: Grifulvin, Grisactin, Fulvicin; 4x/hr  Microsize: cap 125,250mg; tab 250mg; susp125 mg/5mL  Ultramicrosize: tab 125,165,250,330mg  Fungistatik  INDIKASI:  INDIKASI: Microsporum, epidermophyton, trichophyton (kulit, rambut, kuku)

21 ALLYLAMINE & BENZYLAMINE...(1)  PREPARAT:  Terbinafine (Lamisil): oral (250 mg tab 1x/hr); topical (1% cream, gel)  Naftifine (Naftin): topical (1% cream, gel)  Butenafine (Mentax): topical (1% cream)  Fungisid  menghambat enzim squalene epoxidase yg diperlukan dalam sintesis sterol  FARMAKOKINETIK:  first-pass metabolism  bioav me↓ s/ 40%  T ½ panjang krn diakumulasi di skin, nail, fat  lebih efektif untuk onychomicosis disbanding griseofulvin  Plasma level : ↓ dg rifampin; ↑ dg cimetidine

22  INDIKASI:  Onychomycosis  Dermatophytes (t.corporis,t.cruris,t.pedis,t.capitis)  > efektif DD azole  KONTRAINDIKASI:  Px hepatic failure ([plasma] me↑ unpredictable)  Ibu hamil (kategori B) ALLYLAMINE & BENZYLAMINE...(2)

23  PREPARAT:  PREPARAT: Mycostatin  Oral: tab unit  Topical: cream, oint, powd unit/g  Vaginal tab unit  Sulit diserap kulit, GI Tract, vagina  Oral  rasa tidak enak  Indikasi: hanya efektif untuk candidiasis kulit, mukosa vagina & oral TOPICAL DRUGS: Nystatin

24 TERIMA KASIH