Aznan Lelo & Zulkarnain Rangkuty
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
22 Oktober 2009, KBK, TROPMED
Antifungi
ANTIFUNGAL AGENTSDrugs for systemic
infections Polyene Antibiotics Amphotericin-BAzoles
Drugs for superficial infections
Polyenes Candicidin (vagina) NystatinAzoles
Imidazoles Ketokonazole
Triazoles Fluconazole
Flucytosine Pentamidine
NystatinAzoles Imidazoles
Clotrimazole Miconazole
GriseofulvinNaftifine
What are the targets for antifungal therapy?
Cell membraneFungi use principally ergosterol instead of cholesterol
DNA Synthesis
POLYENESGriseofulvin,
Amfoterisin B, Nystatin,
Natamisin
Flusitosin
Cell WallUnlike mammalian cells, fungi have a cell wall
DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999; Introduction to Medical Mycology. Merck and Co. 2001
AZOLESKetokonazol, Flukonazol, Itrakonazol, Mikonazol
Classification of antifungalsTarget Group Examples Mechanism of actionCell membraneSynthesis
Azoles miconazoleketoconazolefluconazoleitaconazole
Block cytochrome P450Mediated C14 demethyl-ation step in biosynthesis of ergosterol,
Cell membraneFunction
Polyenes amphotericin Bnystatin
Bind to sterols in cell membrane, causingleakage of cellular leakage of cellular components and cell death
Nucleic acidSynthesis
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 bio-synthesis
AZOLE ANTIFUNGALSIMIDAZOLES TOPICAL
Clotrimazole Econazole
TRIAZOLES TOPICAL
Terconazole SYSTEMIC
Butoconazole Terconazole
SYSTEMIC Ketoconazole Miconazole
SYSTEMIC Fluconazole Itraconazole
Pharmacokinetic Antifungal Drugs
No Drugs Absorption Distribution Metabolism Excretion
1. AmphoterisinB
- - Urine Billier
2. Fluconazole Urine3. Fluciytosin CNS fluid Urine3. Fluciytosin CNS fluid Urine4. Ketoconazole Urine
Billier5. Griseofulvin Tissue
keratin Urine
Faeces6. Nystatin - Fungal
Sterol - Faeces
7. Salicylic Acid - - - -
Pharmacodynamic Antifungal DrugsNo Drugs Side effects Contraindications Exp.
1. AmphoterisinB
Menggigil, DemamMuntahSakit KepalaHipotensi
MuntahDiareGangguan fungsi hati
Obat pilihan untuk infeksi jamur sistemik yang berat
2. Fluconazole Muntah, DiareGangguan fungsi hati
Gangguan fungsi hatiKehamilan dan laktasiHipersensitivitas
3. Flucytosine Mual, MuntahRashDepresi sum-sum tulang
Gagal GinjalKehamilan dan Laktasi
+ Amfoterisin B =Aktifitasnya
4. Ketoconazole MualGinekomastiaHepatitis Kolestatik
HipersensitivitasKehamilan dan LaktasiPenyakit hepar akut
Ketokonazol merupakan obat pilihanuntuk Blastomikosis
5. Griseofulvin InfectionsSerum SicknessLeukopenia
Kehamilan Obat pilihan untuk infeksidermatofitosis yang berat
6. Nystatin MuntahDiarrhae
Hypersensitivitas
(-) Superinfeksi pada wanita hamil
7. Salisilyc acid Alergi Hipersensitivitas
Asam salisilat bekerja keratolitis, yaitudapat melarutkan lapisan tanduk
Antifungal Clinical ApplicationsNo. Disease Therapy1. Oral Candidiasis Oral : Fluconazole tablet 1 dd 50-100 mg during 1-2 week
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/kgbw4. Criptoccosis Parenteral: Amphoterisin B IV 0,4-0,5 mg/kgbw
5. Blastomicocys Oral : Ketoconazole tablet 1 dd 400 mg during 6-12 month
6. Tinea Pedis Myconazole ointment 2% 1-2 dd during 3-5 weekUng.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolin-vaselin ana)
7. Tinea Unguium (Onicomycosis)
Terbinafine tablet 250 mg/days6 weeks for finger hand, 12 weeks for finger foot
8. Tinea capitis Griseofulvin 500mg/day [tidak lebih dari 10 mg/kgBB/hari]hingga sembuh [6-8 weeks].
9. Ptyriasis versicolor Salisilat acid 5-10% (used in ruam)Ketoconazole cream during 2-3 weeks
Potential drug interactions with systemic antifungal drugs
Drug Amp-B Ketoco Fluco ItracoCorticosteroids +OAD + +Hydrochlorothiazide +Aminoglycosides +Aminoglycosides +Cimetadine + +Rifampin + + +Calcium blockers +Digitalis glycosides + + +Phenytoin + +Theophylline + +Terfenadine + +Isoniazid + +
Mechanisms of antifungal resistance
Target enzyme modification
Ergosterol biosynthetic pathwaypathway
Efflux pumps Drug import
White TC, Marr KA, Bowden RA. Clin Microbiol Review 1998;11:382-402
Anthelminthics
AnthelminticsGroup Examples Clinical use
Benzimidazoles Mebendazole
Albendazole
Thiabendazole
Threadworm (Ent. vermicularis)
Whipworm (Trich. trichuris)
Roundworm (Ascaris lumbrocoides)
Hookworms (Ancylostoma, Necator)
Larva migrans (dog/cat hookworms)Larva migrans (dog/cat hookworms)
Miscellaneous Diethylcarbam-
azine
Ivermectin
Levamisole
Niclosamide
Piperazine
Praziquantel
Filaria (L loa, W. bancrofti, B malayi)
Filaria, especiallyOnchocerca spp.
Roundworms, hookworms
Tapeworms
Roundworms, threadworms
Schistosomes
Obat-obat untuk PenatalaksanaanInfeksi-infeksi Cacing Parasit
Spesies Cacing Obat Pilihan Obat AlternatifNematoda (roundworms)Ascaris lumbricoides(roundworm)
AlbendazolePyrantel pamoate/Mebendazole
Piperazine
Trichuris trichiura(whipworm)
MebendazoleAlbendazole
Oxantel/Pyrantel pamoate
Necator americanus 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(+kortikosteroiduntuk infeksi berat)
Albendazole(+kortikosteroiduntuk infeksi berat)
Trichostrongylus species Pyrantel pamoate/Mebendazole
Albendazole
Obat-obat untuk PenatalaksanaanInfeksi-infeksi Cacing Parasit
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);
Diethylcarbamazine IvermectinBrugia malayi (filariasis); tropical eosinophilia;Loa loa (loiasis)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)
Praziquantel/ Niclosamide
Obat-obat untuk PenatalaksanaanInfeksi-infeksi Cacing Parasit
Spesies Cacing Obat Pilihan Obat Alternatif
Schistosoma haematobium(bilharziasis)
Praziquantel Metrifonate
Schistosoma mansoni Praziquantel Oxamniquine
Schistosoma japonicum PraziquantelClonorchis sinensis Praziquantel AlbendazoleClonorchis sinensis(liver fluke);opisthorchis species
Praziquantel Albendazole
Taenia saginata(beef tapeworm)
Praziquantel/ Niclosamide Mebendazole
Taenia solium(pork tapeworm)
Praziquantel/ Niclosamide
Diphyllobothrium latum(fish tapeworm)
Praziquantel/ Niclosamide
Hymenolepis nana (dwarf tapeworm)
Praziquantel Niclosamide
Mekanisme Kerja Obat-obat yang Dipakai dalam Kemoterapi Kecacingan
Nama Obat Mekanisme Kerja Efek Spesifik
Piperazine Memparalisisotot cacing
Memblokir myoneural junction; agonis gated chloride channels hiperpolarisasi paralisis flasid
IvermectinMemparalisisotot cacing
Memblokir transmisi sinyal-sinyal saraf denganberinteraksi dengan glutamate gated chloride channels
Pyrantel Memparalisisotot cacing
Agonis reseptor asetilkolin nikotinik & menghambat kolinesterase depolarisasi & paralisis spastik
Metrifonate Memparalisis Menginaktivasi asetilkolinesterase & mempotensiasiMetrifonate(Trichlorfon)
Memparalisisotot cacing
Menginaktivasi asetilkolinesterase & mempotensiasiefek-efek kolinergik inhibitori
PraziquantelMemparalisisotot cacing
Meningkatkan permeabilitas membran terhadap Ca2+ memaparkan protein-protein membran diserang antibodi
Niclosamide Menghambatproduksi energiMenghambat fosforilasi oksidatif anaerobik dalammitokondria cacing sintesa ATP
Mebendazole Menghambat produksienergi
Berikatan dengan tubulin & menghambat polimerisasi
Thiabendazole Menghambat produksi energi & fungsi protein
Menghambat fumarat reduktase & sintesa ATP; berikatan dengan tubulin
Diethyl-carbamazine
Mempermudahfagositosis & eliminasi
Meningkatkan kesensitifan mikrofilaria, memerangkapmikrofilaria dalam sistem retikuloendotelial
Antiprotozoa
Classification of antiprotozoals
Group Examples Clinical use
Nitroimidazole Metronidazole
Tinidazole
Entamoeba, Giardia lamblia,
Trichomonas vaginalis, Balantidium
Diamino-
Pyrimidines
Pyrimethamine
Trimethoprim
PCP, T. gondii
Pyrimidines Trimethoprim
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 infected with E. histolyticaas follows:
Anti - ameobic drugsMIXED INFECTION: LUMINAL / SYSTEMIC AMEBICIDAL DRUGS : Metronidazole, Tinidazole, Secnidazole,
Ornidazole Emetine EmetineSYSTEMIC AMEBICIDAL DRUGS : ChloroquineLUMINAL AMEBICIDAL DRUGS : Diloxanide furoate, Iodoquinol, Tetracycline,
Paramomycin.
Asymptomatic cysts carriers Iodoquinol or
Paromomycin or
Diloxanide furoate
Diarrhea / Dysentery Metronidazole +
Anti - ameobic drugs
Diarrhea / Dysentery Metronidazole +
Iodoquinol or
Diloxanide or
Paramomycin
Amebic liver abcess Chloroquine +
Metronidazole
METRONIDAZOLEMixed amebicidal Broad spectrum cidal activity against --- Protozoa
E.histolytica, T.vaginalis, G.lamblia Anaerobic bacteria B.fragilis, C.perfringes, H.pylori,
Cl. difficileCl. difficileMechanism of action : Nitro group is reduced to an intermediate compounds
which causes cytotoxicity by block ETC / damaging DNAPharmacokinetics : Well absorbed from the intestine Widely distributed in the body secretions semen, saliva
and CSF
MetronidazoleAdverse effects : Nausea and metallic taste are most
common
Seizures at high dose Seizures at high doseContra-indications : First trimester of pregnancy Chronic alcoholism
Anti - Ameobic DrugsEmetine : Inhibit protein synthesis by blocking chain
elongation. It is administered by i.m injection. Adverse effects includes cardiotoxicity and Adverse effects includes cardiotoxicity and
neuromuscular weakness.Iodoquinol : Amebicidal against luminal trophozoites and
cysts Adverse effects includes peripheral
neuropathy and optic neuritis.
Anti - Ameobic DrugsDiloxanide 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 drugsMelarsoprol : Trypanosomiasis Trivalent arsenical Mainly used to treat trypanosoma
infections with CNS involvement.infections with CNS involvement. The drug acts by reacting with SH groups
of various enzymes
Anti-protozoal drugsPentamidine Trypanosomiasis Active against trypanosoma and
leshmaniasis and fungus - pneumocystis jirovecijiroveci
Pentamidine interfere with synthesis of RNA, DNA and proteins.
Administered IV or aerosol Nephrotoxicity is the limitation.
Anti-protozoal drugsNifurtimox : Trypanosomiasis Chagas
disease Used in the treatment of Trypanosoma
cruzi infection.cruzi infection. It acts by generating superoxide and
hydrogen peroxide radicals toxic as they lack catalase.
Orally well absorbed
Anti-protozoal drugsLeshmaniasis : Antimonials - Sodium stibogluconate Pentamidine Amphotericin Amphotericin
Anti-protozoal drugsSodium stibogluconate : Leshmaniasis It acts by inhibiting glycolysis and fatty
acid oxidation It is administered i.m or i.v 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 Mites ScabiesBoth are treated by Permethrin topical
Anti-protozoal drugsProtozoal diseases Drugs
Amoebiasis Antiamoebic agentsMalaria Antimalarial drugsTrypanosomiasisChagas disease
NifurtimoxChagas diseaseT. gambienseAfrican Sleeping sickness
Suramin & Pentamidine
T. Rhodesiense - CNS African Sleeping sickness
Melarsoprol
Leishmaniasis StibogluconateToxoplasmosis Pyrimethamine and
Sulfadiazine
Classification of Antimalarials
Group Examples Clinical use
Nitroimidazoles ChloroquineMefloquine
Primaquine
Quinine
Prophylaxis & treatment of malaria
Prophylaxis & treatment of malaria
Treatment P.ovale, P. vivax
Treatment of P. falciparum
Biguanides Proguanil Prophylactic antimalarialBiguanides Proguanil Prophylactic antimalarial
Miscellaneous AtovaquoneHalofantrine
Pyrimethamine
Sulfadoxine
Dapsone
Doxycycline
Artemesin
Treatment of P. falciparum
Treatment of P. falciparum
Prophylaxis & treatment of
P. falciparum
Treatment of P. falciparum
Prophylaxis of P. falciparum
Treatment of P. falciparum
Treatment of malaria
Anti-malarial drugs
Chloroquine most common
Quinine Chloroquine resistant
Pyrimethamine / Sulfonamides
Primaquine Radical cure 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 / 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 parasiteachieve total eradication of parasite
Primaquine + Chloroquine
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