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

Drugs for superficial infections Polyenes Candicidin (vagina) Nystatin Azoles Imidazoles
Clotrimazole Miconazole

Triazoles
Fluconazole

Flucytosine Pentamidine

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 Cell membrane Synthesis Group Azoles Examples miconazole ketoconazole fluconazole itaconazole amphotericin B nystatin Mechanism of action Block cytochrome P450 Mediated C14 demethylation step in biosynthesis of ergosterol, Bind to sterols in cell membrane, causing leakage of cellular components and cell death Deaminated in cell into 5-FU which is incorporated into RNA, causing disturbances of protein synthesis, and inhibits DNA synthesis Bind to microtubule proteins, inhibits mitosis and nucleic acid biosynthesis

Cell membrane Function

Polyenes

Nucleic acid Synthesis

Pyrimidines

flucytosine

Benzofurans

griseofulvin

AZOLE ANTIFUNGALS
IMIDAZOLES TOPICAL
Clotrimazole Econazole Butoconazole Terconazole

TRIAZOLES TOPICAL
Terconazole

SYSTEMIC
Fluconazole Itraconazole

SYSTEMIC
Ketoconazole Miconazole

Pharmacokinetic Antifungal Drugs

No Drugs Absorption Distribution Metabolism Excretion

1. 2. 3. 4. 5. 6. 7.

Amphoterisin B Fluconazole Fluciytosin Ketoconazole Griseofulvin Nystatin Salicylic Acid

CNS fluid Tissue keratin Fungal Sterol -

Urine Billier Urine Urine Urine Billier Urine Faeces Faeces -

Pharmacodynamic Antifungal Drugs

No
1.

Drugs
Amphoterisin B

Side effects
Menggigil, Demam Muntah Sakit Kepala Hipotensi Muntah, Diare Gangguan fungsi hati Mual, Muntah Rash Depresi sum-sum tulang Mual Ginekomastia Hepatitis Kolestatik Infections Serum Sickness Leukopenia Muntah Diarrhae Alergi

Contraindications
Muntah Diare Gangguan fungsi hati Gangguan fungsi hati Kehamilan dan laktasi Hipersensitivitas Gagal Ginjal Kehamilan dan Laktasi Hipersensitivitas Kehamilan dan Laktasi Penyakit hepar akut Kehamilan

Exp.
Obat pilihan untuk infeksi jamur sistemik yang berat

2.

Fluconazole

3.

Flucytosine

+ Amfoterisin B = Aktifitasnya Ketokonazol merupakan obat pilihan untuk Blastomikosis

4.

Ketoconazole

5.

Griseofulvin

Obat pilihan untuk infeksi dermatofitosis yang berat

6. 7.

Nystatin Salisilyc acid

Hyper sensitivitas Hiper sensitivitas

(-) Superinfeksi pada wanita hamil Asam salisilat bekerja keratolitis, yaitu dapat melarutkan lapisan tanduk

Antifungal Clinical Applications

No.
1. 2. 3. 4. 5. 6.

Disease
Oral Candidiasis Vaginal Candidiasis Aspergilosis Criptoccosis Blastomicocys Tinea Pedis

Therapy
Oral : Fluconazole tablet 1 dd 50-100 mg during 1-2 week Ovula: Clotrimazole 200 mg during 3 days or single dose 500 mg Oral: Fluconazole tablet 150 mg single dose Parenteral: Amphotericin B IV 0,5-1,0 mg/kgbw daily Parenteral: Amphoterisin B IV 0,4-0,5 mg/kgbw 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

7. 8. 9.

Tinea Unguium (Onicomycosis) Tinea capitis Ptyriasis versicolor

Potential drug interactions with systemic antifungal drugs

Drug
Corticosteroids OAD Hydrochlorothiazide Aminoglycosides Cimetadine Rifampin Calcium blockers Digitalis glycosides Phenytoin Theophylline Terfenadine Isoniazid + + + + + + + + + + + + + + + + + +

Amp-B
+

Ketoco

Fluco
+ +

Itraco
+

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
Benzimidazoles

Examples
Mebendazole Albendazole Thiabendazole

Clinical use
Threadworm (Ent. vermicularis) Whipworm (Trich. trichuris) Roundworm (Ascaris lumbrocoides) Hookworms (Ancylostoma, Necator) Larva migrans (dog/cat hookworms) Filaria (L loa, W. bancrofti, B malayi) Filaria, especiallyOnchocerca spp. Roundworms, hookworms Tapeworms Roundworms, threadworms Schistosomes

Miscellaneous

Diethylcarbamazine Ivermectin Levamisole Niclosamide Piperazine Praziquantel

Obat-obat untuk Penatalaksanaan Infeksi-infeksi Cacing Parasit

Spesies Cacing
Nematoda (roundworms) Ascaris lumbricoides (roundworm) Trichuris trichiura (whipworm) Necator americanus (hookworm); Ancylostoma duodenale (hookworm) Strongyloides stercoralis (threadworm) Enterobius vermicularis (pinworm) Trichinella spiralis (trichinosis) Trichostrongylus species Albendazole Pyrantel pamoate/ Mebendazole Mebendazole Albendazole Pyrantel pamoate/ Mebendazole/ Albendazole Ivermectin Mebendazole/ Pyrantel pamoate Mebendazole (+kortikosteroid untuk infeksi berat) Pyrantel pamoate/ Mebendazole Thiabendazole, Albendazole Albendazole Albendazole (+kortikosteroid untuk infeksi berat) Albendazole Piperazine

Obat Pilihan

Obat Alternatif

Oxantel/ Pyrantel pamoate

Obat-obat untuk Penatalaksanaan Infeksi-infeksi Cacing Parasit

Spesies Cacing Cutaneous larva migrans (creeping eruption) Angiostrongylus cantonensis Onchocerca volvulus (onchocerciasis) Wuchereria bancrofti (filariasis); Brugia malayi (filariasis); tropical eosinophilia; Loa loa (loiasis) Capillaria philippinensis (intestinal capillariasis) Paragonimus westermani (lung fluke) Fasciola hepatica (sheep liver fluke) Fasciolopsis buski (large intestinal fluke) Heterophyes heterophyes; Metagonimus yokogawai (small intestinal flukes) Obat Pilihan Albendazole/ Ivermectin Thiabendazole Ivermectin Diethylcarbamazine Obat Alternatif Thiabendazole (topikal) Albendazole/Mebendazole Suramin Ivermectin

Albendazole Praziquantel Bithionol/ Triclabendazole Praziquantel/ Niclosamide Praziquantel/ Niclosamide

Mebendazole/Thiabendazole Bithionol

Obat-obat untuk Penatalaksanaan Infeksi-infeksi Cacing Parasit

Spesies Cacing Schistosoma haematobium (bilharziasis) Schistosoma mansoni Schistosoma japonicum Clonorchis sinensis (liver fluke); opisthorchis species Taenia saginata (beef tapeworm) Taenia solium (pork tapeworm) Diphyllobothrium latum (fish tapeworm) Hymenolepis nana (dwarf tapeworm) Obat Pilihan Praziquantel Praziquantel Praziquantel Praziquantel Albendazole Obat Alternatif Metrifonate Oxamniquine

Praziquantel/ Niclosamide Praziquantel/ Niclosamide Praziquantel/ Niclosamide Praziquantel

Mebendazole

Niclosamide

Mekanisme Kerja Obat-obat yang Dipakai dalam Kemoterapi Kecacingan

Nama Obat Piperazine Mekanisme Kerja Memparalisis otot cacing Memparalisis otot cacing Memparalisis otot cacing Memparalisis otot cacing Memparalisis otot cacing Menghambat produksi energi Menghambat produksi energi Menghambat produksi energi & fungsi protein Mempermudah fagositosis & eliminasi Efek Spesifik Memblokir myoneural junction; agonis gated chloride channels hiperpolarisasi paralisis flasid Memblokir transmisi sinyal-sinyal saraf dengan berinteraksi dengan glutamate gated chloride channels Agonis reseptor asetilkolin nikotinik & menghambat kolinesterase depolarisasi & paralisis spastik Menginaktivasi asetilkolinesterase & mempotensiasi efek-efek kolinergik inhibitori Meningkatkan permeabilitas membran terhadap Ca2+ memaparkan protein-protein membran diserang antibodi Menghambat fosforilasi oksidatif anaerobik dalam mitokondria cacing sintesa ATP Berikatan dengan tubulin & menghambat polimerisasi Menghambat fumarat reduktase & sintesa ATP; berikatan dengan tubulin Meningkatkan kesensitifan mikrofilaria, memerangkap mikrofilaria dalam sistem retikuloendotelial

Ivermectin

Pyrantel Metrifonate (Trichlorfon) Praziquantel

Niclosamide Mebendazole Thiabendazole Diethylcarbamazine

Antiprotozoa

Classification of antiprotozoals
Group
Nitroimidazole DiaminoPyrimidines Diamidines Miscellaneous

Examples
Metronidazole Tinidazole Pyrimethamine Trimethoprim Pentamidine Atavoquone Dapsone Diloxanide Amphotericin Co-trimoxazole Sulphadiazine

Clinical use
Entamoeba, Giardia lamblia, Trichomonas vaginalis, Balantidium PCP, T. gondii PCP, Trypanosoma spp, Leishmania spp. 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 Iodoquinol or Paromomycin or Diloxanide furoate Metronidazole + Iodoquinol or Diloxanide or Paramomycin Chloroquine + Metronidazole

Diarrhea / Dysentery

Amebic liver abcess

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

Anti-protozoal drugs
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.

Anti-protozoal drugs
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

Anti-protozoal drugs
Leshmaniasis : Antimonials - Sodium stibogluconate Pentamidine Amphotericin

Anti-protozoal drugs
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

Anti-protozoal drugs
Protozoal diseases Amoebiasis Malaria Trypanosomiasis Chagas disease T. gambiense African Sleeping sickness T. Rhodesiense - CNS African Sleeping sickness Leishmaniasis Toxoplasmosis Drugs Antiamoebic agents Antimalarial drugs Nifurtimox Suramin & Pentamidine Melarsoprol Stibogluconate Pyrimethamine and Sulfadiazine

Classification of Antimalarials
Group Nitroimidazoles Examples
Chloroquine Mefloquine Primaquine Quinine Proguanil Atovaquone Halofantrine Pyrimethamine Sulfadoxine Dapsone Doxycycline Artemesin

Clinical use
Prophylaxis & treatment of malaria Prophylaxis & treatment of malaria Treatment P.ovale, P. vivax Treatment of P. falciparum Prophylactic antimalarial 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

Biguanides Miscellaneous

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