40324512 Tmd175 Slide Pharmacology of Antifungi Anthelminthics Antiprotozoal

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


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)



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)


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

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



Prophylaxis & treatment of

P. falciparum


Prophylaxis 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

40324512 Tmd175 Slide Pharmacology of Antifungi Anthelminthics Antiprotozoal

Documents

cell membranefungi

fluconazole urine3

fluconazole muntah

fluconazole tablet

antifungal therapy

flucytosine mual

salicylic acid

nystatin fungalsterol