Anti-fungal

Pharmacology

Elly Nurus Sakinah

Lab Farmakologi FKUJ
2014
Types of fungal infections - Mycoses

 Superficial mycoses
 Affect the skin, hair and nails

 Subcutaneous mycoses (tropical)

 Affect the muscle and connective tissue immediately
below the skin
 Systemic (invasive) mycoses
 Involve the internal organs

 Primary vs. opportunistic

 What are the targets for antifungal
therapy?
Cell membrane
Fungi use principally ergosterol
instead of cholesterol

DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.

Cell Wall
Unlike mammalian cells, fungi
have a cell wall

Atlas of fungal Infections, Richard Diamond Ed. 1999

Introduction to Medical Mycology. Merck and Co. 2001
Target of antifungal drugs
Drugs for systemic fungal
infections

 Amphotericin B
 Flucytocine (5-FC)
 Azole
 Echinocandins
Amphotericin B
 Pharmacokinetic
 Is a polyene antibiotic  amphipathic (both

hydrophilic and lipophilic)

 A:Poorly absorbed from GIT  i.v ; topical 

formulation : nonlipid colloidal suspension, lipid

complex or liposomal
 D : CNS

 M : slow hepatic metabolism  2 wk

 E : urine, not dialyzable  dosage modification for

renal dysfunction
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 7

POLYENE: Amphotericin B...(2)

 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

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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: mutasi enzim cytosine

deaminase/permease
 FARMAKOKINETIK: abs cepat per oral,
distr luas (CNS,mata,tract urinary), eliminasi
lewat urine, tidak perlu penyesuiaian dosis
pada px dg gangguan ginjal 9
FLUCYTOSINE...(2)
 INDIKASI:
 Candidiasis sistemik, cryptococcus

 Spektrum antifungal sempit  Kombinasi dg

amphotericin B atau dg triazole  uptake
flucytosine dr plasma membran me↑

 TOKSISITAS: supresi bone marrow (leukopenia,

thrombositopenia), disfgs hepar

 KONTRA INDIKASI: Bumil

 PREPARAT: Ancobon (cap 250, 500mg; 4x/hr)
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AZOLE
 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
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 Azoles - Mechanism

 In fungi, the cytochrome P450-

enzyme lanosterol 14-a
demethylase is responsible for the
conversion of lanosterol to
ergosterol
 Azoles bind to lanosterol 14a-
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)
FLUCONAZOLE
 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)

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ITRACONAZOLE
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

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ECHINOCANDIN...(1)
 Glucan synthase inhibitor 
menghambat sintesis dinding sel jamur

 PREPARAT: Caspofungin (Cancidas: 50, 70

mg), Anidulafungin, Micafungin  iv 1x/hr

 Fungistatic (Aspergillus spp)

Fungicidal (Candida spp)
 FARMAKOKINETIK: ik prot ↑; distr pd CSF
<
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Systemic drugs for superficial
fungal infection

 Griseofulvine
 Terbinafine
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: abs ↑ (makanan b’lemak);
enzim inducer (kontrasepsi oral low-estrogen)

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GRISEOFULVIN ...(2)
 PREPARAT: Grifulvin, Grisactin, Fulvicin; 4x/hr
 Microsize: cap 125,250mg; tab 250mg; susp125
mg/5mL
 Ultramicrosize: tab 125,165,250,330mg

 Fungistatik
 INDIKASI: Microsporum, epidermophyton,
trichophyton (kulit, rambut, kuku)

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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 21
ALLYLAMINE &
BENZYLAMINE...(2)
 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)

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TOPICAL DRUGS:
Nystatin
 PREPARAT: Mycostatin
 Oral: tab 500.000 unit

 Topical: cream, oint, powd 100.000

unit/g
 Vaginal tab 100.000 unit

 Sulit diserap kulit, GI Tract, vagina

 Oral  rasa tidak enak

 Indikasi: hanya efektif untuk candidiasis

kulit, mukosa vagina & oral
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TERIMA KASIH

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