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Aznan Lelo & Zulkarnain Rangkuty
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
22 Oktober 2009, KBK, TROPMED
Antifungi
ANTIFUNGAL AGENTS
Drugs for systemic
infections
Polyene Antibiotics
• Amphotericin-B
Azoles
• Imidazoles
– Ketokonazole
• Triazoles
– Fluconazole
Flucytosine
Pentamidine
Drugs for superficial
infections
Polyenes
• Candicidin (vagina)
• Nystatin
Azoles
• Imidazoles
– Clotrimazole
– Miconazole
Griseofulvin
Naftifine
What are the targets for antifungal
therapy?
POLYENES
Cell membrane
Griseofulvin,
Amfoterisin B,
Nystatin,
Natamisin
Fungi use principally ergosterol
instead of cholesterol
DNA Synthesis
Flusitosin
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.
Cell Wall
Unlike mammalian cells, fungi
have a cell wall
AZOLES
Ketokonazol,
Flukonazol,
Itrakonazol,
Mikonazol
Atlas of fungal Infections, Richard Diamond Ed. 1999; Introduction to Medical Mycology. Merck and Co. 2001
Classification of antifungals
Target
Group
Examples
Mechanism of action
Cell membrane
Synthesis
Azoles
miconazole
ketoconazole
fluconazole
itaconazole
Block cytochrome P450
Mediated C14 demethylation step in biosynthesis
of ergosterol,
Cell membrane
Function
Polyenes
amphotericin B
nystatin
Bind to sterols in cell
membrane, causing
leakage of cellular
components and cell
death
Nucleic acid
Synthesis
Pyrimidines
flucytosine
Deaminated in cell into 5-FU which
is incorporated into RNA, causing
disturbances of protein synthesis,
and inhibits DNA synthesis
Benzofurans
griseofulvin
Bind to microtubule proteins, inhibits
mitosis and nucleic acid biosynthesis
AZOLE ANTIFUNGALS
IMIDAZOLES
TOPICAL
Clotrimazole
Econazole
Butoconazole
Terconazole
SYSTEMIC
Ketoconazole
Miconazole
TRIAZOLES
TOPICAL
Terconazole
SYSTEMIC
Fluconazole
Itraconazole
Pharmacokinetic Antifungal Drugs
No
Drugs
Absorption
Distribution
Metabolism
Excretion
1.
Amphoterisin
B
-
√
-
Urine
Billier
2.
Fluconazole
√
√
√
Urine
3.
Fluciytosin
√
CNS fluid
√
Urine
4.
Ketoconazole
√
√
√
Urine
Billier
5.
Griseofulvin
√
Tissue
keratin
√
Urine
Faeces
6.
Nystatin
-
Fungal
Sterol
-
Faeces
7.
Salicylic Acid
-
-
-
-
Pharmacodynamic Antifungal Drugs
No
Drugs
Side effects
Contraindications
Exp.
1.
Amphoterisin
B
Menggigil, Demam
Muntah
Sakit Kepala
Hipotensi
Muntah
Diare
Gangguan fungsi hati
Obat pilihan untuk infeksi jamur
sistemik yang berat
2.
Fluconazole
Muntah,
Diare
Kehamilan dan laktasi
Hipersensitivitas
3.
Flucytosine
Mual, Muntah
Rash
Depresi sum-sum tulang
Gagal Ginjal
Kehamilan dan Laktasi
+ Amfoterisin B =
Aktifitasnya ↑
4.
Ketoconazole
Mual
Ginekomastia
Hepatitis Kolestatik
Hipersensitivitas
Kehamilan dan Laktasi
Penyakit hepar akut
Ketokonazol merupakan obat pilihan
untuk Blastomikosis
5.
Griseofulvin
Infections
Serum Sickness
Leukopenia
Kehamilan
Obat pilihan untuk infeksi
dermatofitosis yang berat
6.
Nystatin
Muntah
Diarrhae
Hyper
sensitivitas
(-) Superinfeksi
√ pada wanita hamil
7.
Salisilyc acid
Alergi
Hiper
sensitivitas
Asam salisilat bekerja keratolitis, yaitu
dapat melarutkan lapisan tanduk
Antifungal Clinical Applications
No.
Disease
Therapy
1.
Oral Candidiasis
2.
Vaginal
Candidiasis
Ovula: Clotrimazole 200 mg during 3 days or single dose 500 mg
Oral: Fluconazole tablet 150 mg single dose
3.
Aspergilosis
Parenteral: Amphotericin B IV 0,5-1,0 mg/kgbw daily
4.
Criptoccosis
Parenteral: Amphoterisin B IV 0,4-0,5 mg/kgbw
5.
Blastomicocys
6.
Tinea Pedis
7.
Tinea Unguium
(Onicomycosis)
8.
Tinea capitis
9.
Ptyriasis versicolor
Oral : Fluconazole tablet 1 dd 50-100 mg during 1-2 week
Oral : Ketoconazole tablet 1 dd 400 mg during 6-12 month
Myconazole ointment 2% 1-2 dd during 3-5 week
Ung.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolinvaselin ana)
Terbinafine tablet 250 mg/days
6 weeks for finger hand, 12 weeks for finger foot
Griseofulvin 500mg/day [tidak lebih dari 10 mg/kgBB/hari]
hingga sembuh [6-8 weeks].
Salisilat acid 5-10% (used in ruam)
Ketoconazole cream during 2-3 weeks
Potential drug interactions with
systemic antifungal drugs
Drug
Fluco
Itraco
OAD
+
+
Hydrochlorothiazide
+
Corticosteroids
Aminoglycosides
Amp-B
Ketoco
+
+
Cimetadine
Rifampin
+
+
+
+
+
Calcium blockers
Digitalis glycosides
Phenytoin
+
+
+
+
+
+
Theophylline
+
+
Terfenadine
+
+
Isoniazid
+
+
Mechanisms of antifungal resistance
• Target enzyme
modification
• Ergosterol biosynthetic
pathway
• Efflux pumps
• Drug import
White TC, Marr KA, Bowden RA.
Clin Microbiol Review 1998;11:382-402
Anthelminthics
Anthelmintics
Group
Examples
Clinical use
Benzimidazoles
Mebendazole
Albendazole
Thiabendazole
Threadworm (Ent. vermicularis)
Whipworm (Trich. trichuris)
Roundworm (Ascaris lumbrocoides)
Hookworms (Ancylostoma, Necator)
Larva migrans (dog/cat hookworms)
Miscellaneous
Diethylcarbamazine
Ivermectin
Levamisole
Niclosamide
Piperazine
Praziquantel
Filaria (L loa, W. bancrofti, B malayi)
Filaria, especiallyOnchocerca spp.
Roundworms, hookworms
Tapeworms
Roundworms, threadworms
Schistosomes
Obat-obat untuk Penatalaksanaan
Infeksi-infeksi Cacing Parasit
Spesies Cacing
Obat Pilihan
Obat Alternatif
Nematoda (roundworms)
Ascaris lumbricoides
(roundworm)
Albendazole
Pyrantel pamoate/
Mebendazole
Piperazine
Trichuris trichiura
(whipworm)
Mebendazole
Albendazole
Oxantel/
Pyrantel pamoate
Necator americanus
(hookworm);
Ancylostoma duodenale
(hookworm)
Pyrantel pamoate/
Mebendazole/
Albendazole
Strongyloides stercoralis
(threadworm)
Ivermectin
Thiabendazole,
Albendazole
Enterobius vermicularis
(pinworm)
Mebendazole/
Pyrantel pamoate
Albendazole
Trichinella spiralis
(trichinosis)
Mebendazole
(+kortikosteroid
untuk infeksi berat)
Albendazole
(+kortikosteroid
untuk infeksi berat)
Trichostrongylus species
Pyrantel pamoate/
Mebendazole
Albendazole
Spesies Cacing
Obat Pilihan
Obat Alternatif
Cutaneous larva migrans
(creeping eruption)
Albendazole/ Ivermectin
Thiabendazole (topikal)
Angiostrongylus cantonensis
Thiabendazole
Albendazole/Mebendazole
Onchocerca volvulus
(onchocerciasis)
Ivermectin
Suramin
Wuchereria bancrofti (filariasis);
Brugia malayi (filariasis);
tropical eosinophilia;
Loa loa (loiasis)
Diethylcarbamazine
Ivermectin
Capillaria philippinensis
(intestinal capillariasis)
Albendazole
Mebendazole/Thiabendazole
Paragonimus westermani
(lung fluke)
Praziquantel
Bithionol
Fasciola hepatica
(sheep liver fluke)
Bithionol/ Triclabendazole
Fasciolopsis buski
(large intestinal fluke)
Praziquantel/ Niclosamide
Heterophyes heterophyes;
Metagonimus yokogawai
(small intestinal flukes)
Spesies Cacing
Obat Pilihan
Obat Alternatif
Schistosoma haematobium
(bilharziasis)
Praziquantel
Metrifonate
Schistosoma mansoni
Praziquantel
Oxamniquine
Schistosoma japonicum
Praziquantel
Clonorchis sinensis
(liver fluke);
opisthorchis species
Praziquantel
Albendazole
Taenia saginata
(beef tapeworm)
Mebendazole
Taenia solium
(pork tapeworm)
Diphyllobothrium latum
(fish tapeworm)
Hymenolepis nana
(dwarf tapeworm)
Praziquantel
Niclosamide
Mekanisme Kerja Obat-obat yang Dipakai
dalam Kemoterapi Kecacingan
Nama Obat
Mekanisme Kerja
Efek Spesifik
Memparalisis
otot cacing
Memblokir myoneural junction; agonis gated chloride
channels hiperpolarisasi paralisis flasid
Memparalisis
otot cacing
Memblokir transmisi sinyal-sinyal saraf dengan
berinteraksi dengan glutamate gated chloride
channels
Pyrantel
Memparalisis
otot cacing
Agonis reseptor asetilkolin nikotinik & menghambat
kolinesterase depolarisasi & paralisis spastik
Metrifonate
(Trichlorfon)
Memparalisis
otot cacing
Menginaktivasi asetilkolinesterase & mempotensiasi
efek-efek kolinergik inhibitori
Praziquantel
Memparalisis
otot cacing
Meningkatkan permeabilitas membran terhadap Ca2+
memaparkan protein-protein membran diserang antibodi
Niclosamide
Menghambat
produksi energi
Menghambat fosforilasi oksidatif anaerobik dalam
mitokondria cacing sintesa ATP
Mebendazole
Menghambat produksi
energi
Berikatan dengan tubulin & menghambat polimerisasi
Thiabendazole
Menghambat produksi
energi & fungsi protein
Menghambat fumarat reduktase & sintesa ATP;
berikatan dengan tubulin
Diethylcarbamazine
Mempermudah
fagositosis & eliminasi
Meningkatkan kesensitifan mikrofilaria, memerangkap
mikrofilaria dalam sistem retikuloendotelial
Piperazine
Ivermectin
Antiprotozoa
Classification of antiprotozoals
Group
Examples
Clinical use
Nitroimidazole
Metronidazole
Tinidazole
Entamoeba, Giardia lamblia,
Trichomonas vaginalis, Balantidium
DiaminoPyrimidines
Pyrimethamine
Trimethoprim
PCP, T. gondii
Diamidines
Pentamidine
PCP, Trypanosoma spp, Leishmania spp.
Miscellaneous
Atavoquone
Dapsone
Diloxanide
Amphotericin
Co-trimoxazole
Sulphadiazine
PCP, ? cerebral toxoplasmosis
PCP prophylaxis
luminal asymptomatic amoebiasis
Leishmania spp.
Isospora, cyclospora
T. gondii
A person
becomes
infected with
E. histolytica
as follows:
Anti - ameobic drugs
MIXED INFECTION:
• LUMINAL / SYSTEMIC AMEBICIDAL DRUGS :
• Metronidazole, Tinidazole, Secnidazole,
Ornidazole
• Emetine
SYSTEMIC AMEBICIDAL DRUGS :
• Chloroquine
LUMINAL AMEBICIDAL DRUGS :
• Diloxanide furoate, Iodoquinol, Tetracycline,
Paramomycin.
Anti - ameobic drugs
Asymptomatic cysts carriers
Diarrhea / Dysentery
Amebic liver abcess
Iodoquinol or
Paromomycin or
Diloxanide furoate
Metronidazole +
Iodoquinol or
Diloxanide or
Paramomycin
Chloroquine +
Metronidazole
METRONIDAZOLE
Mixed amebicidal
•
Broad spectrum cidal activity against --- Protozoa –
E.histolytica, T.vaginalis, G.lamblia
•
Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori,
Cl. difficile
Mechanism of action :
• Nitro group is reduced to an intermediate compounds
which causes cytotoxicity by block ETC / damaging DNA
Pharmacokinetics :
• Well absorbed from the intestine
• Widely distributed in the body secretions – semen, saliva
and CSF
Metronidazole
Adverse effects :
• Nausea and metallic taste are most
common
• Seizures at high dose
Contra-indications :
• First trimester of pregnancy
• Chronic alcoholism
Anti - Ameobic Drugs
Emetine :
• Inhibit protein synthesis by blocking chain
elongation.
• It is administered by i.m injection.
• Adverse effects includes cardiotoxicity and
neuromuscular weakness.
Iodoquinol :
• Amebicidal against luminal trophozoites and
cysts
• Adverse effects includes – peripheral
neuropathy and optic neuritis.
Anti - Ameobic Drugs
Diloxanide furoate :
• Effective luminal ameobicidal – kills trophozoites
• High cure rates in mild intestinal amoebiasis and
asymptomatic cyst passers
Paromomycin :
• Aminoglycosides which is not absorbed from
GIT.
• Effective against luminal forms of E. Histolytica
– directly
• It acts indirectly by reducing the intestinal flora
also.
Anti-protozoal drugs
Melarsoprol : Trypanosomiasis
• Trivalent arsenical
• Mainly used to treat trypanosoma
infections with CNS involvement.
• The drug acts by reacting with SH groups
of various enzymes
Pentamidine Trypanosomiasis
• Active against trypanosoma and
leshmaniasis and fungus - pneumocystis
jiroveci
• Pentamidine interfere with synthesis of
RNA, DNA and proteins.
• Administered IV or aerosol
• Nephrotoxicity is the limitation.
Nifurtimox : Trypanosomiasis Chagas
disease
• Used in the treatment of Trypanosoma
cruzi infection.
• It acts by generating superoxide and
hydrogen peroxide radicals – toxic as they
lack catalase.
• Orally well absorbed
Leshmaniasis :
• Antimonials - Sodium stibogluconate
• Pentamidine
• Amphotericin
Sodium stibogluconate : Leshmaniasis
• It acts by inhibiting glycolysis and fatty
acid oxidation
• It is administered i.m or i.v
• Cardiac arrhythmia and nephrotoxicity are
adverse effects.
Drugs for ectoparasites
• Ectoparasites infestations are caused by
organisms that live on the skin and hair.
• Lice – Peduculosis
• Mites – Scabies
Both are treated by Permethrin – topical
Protozoal diseases
Amoebiasis
Malaria
Trypanosomiasis
Chagas disease
T. gambiense
African Sleeping sickness
T. Rhodesiense - CNS
African Sleeping sickness
Leishmaniasis
Drugs
Antiamoebic agents
Antimalarial drugs
Nifurtimox
Toxoplasmosis
Pyrimethamine and
Sulfadiazine
Suramin & Pentamidine
Melarsoprol
Stibogluconate
Classification of Antimalarials
Group
Nitroimidazoles
Biguanides
Miscellaneous
Examples
Clinical use
Chloroquine
Mefloquine
Primaquine
Quinine
Prophylaxis & treatment of malaria
Prophylaxis & treatment of malaria
Treatment P.ovale, P. vivax
Treatment of P. falciparum
Proguanil
Prophylactic antimalarial
Atovaquone
Halofantrine
Pyrimethamine
Prophylaxis & treatment of
P. falciparum
Prophylaxis of P. falciparum
Treatment of malaria
Sulfadoxine
Dapsone
Doxycycline
Artemesin
Anti-malarial drugs
•
•
•
•
•
Chloroquine – most common
Quinine – Chloroquine resistant
Pyrimethamine / Sulfonamides
Primaquine – Radical cure
New drugs - Mefloquine, Artimisinin ,
Halofantrine
Anti-malarial drugs
Drugs for the Exo-erythrocytic phase (liver)
and gametocytes :
• Primaquine
Drugs to suppress erythrocytic phase /
Schizontocides / Clinical cure :
• Chloroquine, Quinine, Pyrimethamine,
Mefloquine, Artemisinin
Anti-malarial drugs
Radical cure : Exoerythrocytic phase
(hypnozoites) with the clinical cure thus
achieve total eradication of parasite
• Primaquine + Chloroquine

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