aznan lelo & zulkarnain...
TRANSCRIPT
Aznan Lelo & Zulkarnain Rangkuty
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
22 Oktober 2009, KBK, TROPMED
ANTIFUNGAL AGENTS
Drugs for systemic infections
Polyene Antibiotics
• Amphotericin-B
Azoles
Drugs for superficial infections
Polyenes
• Candicidin (vagina)
• NystatinAzoles
• Imidazoles– Ketokonazole
• Triazoles– Fluconazole
Flucytosine
Pentamidine
• Nystatin
Azoles
• Imidazoles– Clotrimazole
– Miconazole
Griseofulvin
Naftifine
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 action
Cell membraneSynthesis
Azoles miconazole
ketoconazole
fluconazole
itaconazole
Block cytochrome P450
Mediated C14 demethyl-
ation step in biosynthesis
of ergosterol,
Cell membraneFunction
Polyenes amphotericin B
nystatin
Bind to sterols in cell
membrane, causing
leakage 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 ANTIFUNGALS
IMIDAZOLES
� 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 √ √ √ Urine
3. Fluciytosin √ CNS fluid √ Urine3. Fluciytosin √ CNS fluid √ Urine
4. Ketoconazole √ √ √ Urine Billier
5. Griseofulvin √ Tissue keratin
√ UrineFaeces
6. Nystatin - FungalSterol
- 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
Gangguan fungsi hati
Gangguan fungsi hati
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 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 week
Ung.Whitfield (Benzoic Acid 5 %, Salisilyc acid 5% in lanolin-
vaselin ana)
7. Tinea Unguium
(Onicomycosis)
Terbinafine tablet 250 mg/days
6 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 Itraco
Corticosteroids +
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
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)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 Alternatif
Nematoda (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 Praziquantel
Clonorchis 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
PiperazineMemparalisisotot cacing
Memblokir myoneural junction; agonis gated chloride channels � hiperpolarisasi � paralisis flasid
IvermectinMemparalisisotot cacing
Memblokir transmisi sinyal-sinyal saraf denganberinteraksi dengan glutamate gated chloride channels
PyrantelMemparalisisotot 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
NiclosamideMenghambatproduksi energi
Menghambat fosforilasi oksidatif anaerobik dalammitokondria cacing � sintesa ATP
MebendazoleMenghambat produksienergi
Berikatan dengan tubulin & menghambat polimerisasi
ThiabendazoleMenghambat produksi energi & fungsi protein
Menghambat fumarat reduktase & sintesa ATP; berikatan dengan tubulin
Diethyl-carbamazine
Mempermudahfagositosis & eliminasi
Meningkatkan kesensitifan mikrofilaria, memerangkapmikrofilaria dalam sistem retikuloendotelial
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
Anti - ameobic drugs
MIXED INFECTION:
• LUMINAL / SYSTEMIC AMEBICIDAL DRUGS :
• Metronidazole, Tinidazole, Secnidazole, Ornidazole
• Emetine• Emetine
SYSTEMIC AMEBICIDAL DRUGS :
• Chloroquine
LUMINAL 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
METRONIDAZOLE
Mixed amebicidal• Broad spectrum cidal activity against --- Protozoa –
E.histolytica, T.vaginalis, G.lamblia
• Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori,
Cl. difficileCl. 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• 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 • 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.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 jirovecijiroveci
• 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.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• Amphotericin
Anti-protozoal drugs
Sodium 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 – Scabies
Both are treated by Permethrin – topical
Anti-protozoal drugs
Protozoal diseases Drugs
Amoebiasis Antiamoebic agents
Malaria Antimalarial drugs
TrypanosomiasisChagas disease
NifurtimoxChagas disease
T. gambienseAfrican Sleeping sickness
Suramin & Pentamidine
T. Rhodesiense - CNS African Sleeping sickness
Melarsoprol
Leishmaniasis Stibogluconate
Toxoplasmosis Pyrimethamine and Sulfadiazine
Classification of Antimalarials
Group Examples Clinical use
Nitroimidazoles Chloroquine
Mefloquine
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 Atovaquone
Halofantrine
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