Aznan Lelo & Zulkarnain Rangkuty

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
22 Oktober 2009, KBK, TROPMED
Antifungi
 ANTIFUNGAL AGENTS
Drugs for systemic Drugs for superficial
infections infections
Polyene Antibiotics Polyenes
• Amphotericin-B • Candicidin (vagina)
Azoles • Nystatin
• Imidazoles Azoles
– Ketokonazole • Imidazoles
• Triazoles – Clotrimazole
– Fluconazole – Miconazole
Flucytosine Griseofulvin
Pentamidine Naftifine
 What are the targets for antifungal
therapy? POLYENES
Griseofulvin,
Amfoterisin B,
Nystatin,
Cell membrane Natamisin
Fungi use principally ergosterol
instead of cholesterol

Flusitosin
DNA Synthesis
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 Azoles miconazole Block cytochrome P450
Synthesis ketoconazole Mediated C14 demethyl-
fluconazole ation step in biosynthesis
itaconazole of ergosterol,
Cell membrane Polyenes amphotericin B Bind to sterols in cell
Function nystatin membrane, causing
leakage of cellular
components and cell
death
Nucleic acid Pyrimidines flucytosine Deaminated in cell into 5-FU which
Synthesis 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 TRIAZOLES

TOPICAL
TOPICAL
 Clotrimazole  Terconazole
 Econazole
SYSTEMIC
 Butoconazole
 Fluconazole
 Terconazole
 Itraconazole

SYSTEMIC
 Ketoconazole
 Miconazole
 Pharmacokinetic Antifungal Drugs

No Drugs Absorption Distribution Metabolism Excretion

1. Amphoterisin - √ - Urine
B Billier
2. Fluconazole √ √ √ Urine
3. Fluciytosin √ CNS fluid √ Urine
4. Ketoconazole √ √ √ Urine
Billier
5. Griseofulvin √ Tissue √ Urine
keratin Faeces
6. Nystatin - Fungal - Faeces
Sterol
7. Salicylic Acid - - - -
Pharmacodynamic Antifungal Drugs
No Drugs Side effects Contraindications Exp.
1. Amphoterisin Menggigil, Demam Muntah Obat pilihan untuk infeksi jamur
B Muntah Diare sistemik yang berat
Sakit Kepala Gangguan fungsi hati
Hipotensi
2. Fluconazole Muntah, Gangguan fungsi hati
Diare Kehamilan dan laktasi
Gangguan fungsi hati Hipersensitivitas
3. Flucytosine Mual, Muntah Gagal Ginjal + Amfoterisin B =
Rash Kehamilan dan Laktasi Aktifitasnya ↑
Depresi sum-sum tulang
4. Ketoconazole Mual Hipersensitivitas Ketokonazol merupakan obat pilihan
Ginekomastia Kehamilan dan Laktasi untuk Blastomikosis
Hepatitis Kolestatik Penyakit hepar akut
5. Griseofulvin Infections Kehamilan Obat pilihan untuk infeksi
Serum Sickness dermatofitosis yang berat
Leukopenia
6. Nystatin Muntah Hyper (-) Superinfeksi
Diarrhae sensitivitas √ pada wanita hamil
7. Salisilyc acid Alergi Hiper Asam salisilat bekerja keratolitis, yaitu
sensitivitas 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 Ovula: Clotrimazole 200 mg during 3 days or single dose 500 mg
Candidiasis 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 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 Terbinafine tablet 250 mg/days
(Onicomycosis) 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 +
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 Threadworm (Ent. vermicularis)
Albendazole Whipworm (Trich. trichuris)
Thiabendazole Roundworm (Ascaris lumbrocoides)
Hookworms (Ancylostoma, Necator)
Larva migrans (dog/cat hookworms)
Miscellaneous Diethylcarbam- Filaria (L loa, W. bancrofti, B malayi)
azine
Ivermectin Filaria, especiallyOnchocerca spp.
Levamisole Roundworms, hookworms
Niclosamide Tapeworms
Piperazine Roundworms, threadworms
Praziquantel Schistosomes
 Obat-obat untuk Penatalaksanaan
Infeksi-infeksi Cacing Parasit
Spesies Cacing Obat Pilihan Obat Alternatif
Nematoda (roundworms)

Ascaris lumbricoides Albendazole Piperazine

(roundworm) Pyrantel pamoate/
Mebendazole
Trichuris trichiura Mebendazole Oxantel/
(whipworm) Albendazole Pyrantel pamoate
Necator americanus Pyrantel pamoate/
(hookworm); Mebendazole/
Ancylostoma duodenale Albendazole
(hookworm)
Strongyloides stercoralis Ivermectin Thiabendazole,
(threadworm) Albendazole
Enterobius vermicularis Mebendazole/ Albendazole
(pinworm) Pyrantel pamoate
Trichinella spiralis Mebendazole Albendazole
(trichinosis) (+kortikosteroid (+kortikosteroid
untuk infeksi berat) untuk infeksi berat)
Trichostrongylus species Pyrantel pamoate/ Albendazole
Mebendazole
 Obat-obat untuk Penatalaksanaan
Infeksi-infeksi Cacing Parasit
Spesies Cacing Obat Pilihan Obat Alternatif

Cutaneous larva migrans Albendazole/ Ivermectin Thiabendazole (topikal)

(creeping eruption)
Angiostrongylus cantonensis Thiabendazole Albendazole/Mebendazole

Onchocerca volvulus Ivermectin Suramin

(onchocerciasis)
Wuchereria bancrofti (filariasis); Diethylcarbamazine Ivermectin
Brugia malayi (filariasis);
tropical eosinophilia;
Loa loa (loiasis)
Capillaria philippinensis Albendazole Mebendazole/Thiabendazole
(intestinal capillariasis)
Paragonimus westermani Praziquantel Bithionol
(lung fluke)
Fasciola hepatica Bithionol/ Triclabendazole
(sheep liver fluke)
Fasciolopsis buski Praziquantel/ Niclosamide
(large intestinal fluke)
Heterophyes heterophyes; Praziquantel/ Niclosamide
Metagonimus yokogawai
(small intestinal flukes)
 Obat-obat untuk Penatalaksanaan
Infeksi-infeksi Cacing Parasit
Spesies Cacing Obat Pilihan Obat Alternatif

Schistosoma haematobium Praziquantel Metrifonate

(bilharziasis)
Schistosoma mansoni Praziquantel Oxamniquine

Schistosoma japonicum Praziquantel

Clonorchis sinensis Praziquantel Albendazole

(liver fluke);
opisthorchis species
Taenia saginata Praziquantel/ Niclosamide Mebendazole
(beef tapeworm)
Taenia solium Praziquantel/ Niclosamide
(pork tapeworm)
Diphyllobothrium latum Praziquantel/ Niclosamide
(fish tapeworm)
Hymenolepis nana Praziquantel Niclosamide
(dwarf tapeworm)
 Mekanisme Kerja Obat-obat yang Dipakai
dalam Kemoterapi Kecacingan
Nama Obat Mekanisme Kerja Efek Spesifik
Memparalisis Memblokir myoneural junction; agonis gated chloride
Piperazine
otot cacing channels  hiperpolarisasi  paralisis flasid
Memparalisis Memblokir transmisi sinyal-sinyal saraf dengan
Ivermectin otot cacing berinteraksi dengan glutamate gated chloride
channels
Memparalisis Agonis reseptor asetilkolin nikotinik & menghambat
Pyrantel
otot cacing kolinesterase  depolarisasi & paralisis spastik
Metrifonate Memparalisis Menginaktivasi asetilkolinesterase & mempotensiasi
(Trichlorfon) otot cacing efek-efek kolinergik inhibitori
Memparalisis Meningkatkan permeabilitas membran terhadap Ca2+
Praziquantel otot cacing  memaparkan protein-protein membran 
diserang antibodi
Menghambat Menghambat fosforilasi oksidatif anaerobik dalam
Niclosamide
produksi energi mitokondria cacing  sintesa ATP
Menghambat produksi Berikatan dengan tubulin & menghambat polimerisasi
Mebendazole
energi
Menghambat produksi Menghambat fumarat reduktase & sintesa ATP;
Thiabendazole
energi & fungsi protein berikatan dengan tubulin
Diethyl- Mempermudah Meningkatkan kesensitifan mikrofilaria, memerangkap
carbamazine fagositosis & eliminasi mikrofilaria dalam sistem retikuloendotelial
Antiprotozoa
 Classification of antiprotozoals
Group Examples Clinical use
Nitroimidazole Metronidazole Entamoeba, Giardia lamblia,
Tinidazole Trichomonas vaginalis, Balantidium
Diamino- Pyrimethamine PCP, T. gondii
Pyrimidines Trimethoprim
Diamidines Pentamidine PCP, Trypanosoma spp, Leishmania spp.
Miscellaneous Atavoquone PCP, ? cerebral toxoplasmosis
Dapsone PCP prophylaxis
Diloxanide luminal asymptomatic amoebiasis
Amphotericin Leishmania spp.
Co-trimoxazole Isospora, cyclospora
Sulphadiazine 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
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. 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 Drugs
Amoebiasis Antiamoebic agents
Malaria Antimalarial drugs
Trypanosomiasis Nifurtimox
Chagas disease
T. gambiense Suramin & Pentamidine
African Sleeping sickness
T. Rhodesiense - CNS Melarsoprol
African Sleeping sickness
Leishmaniasis Stibogluconate
Toxoplasmosis Pyrimethamine and
Sulfadiazine
 Classification of Antimalarials
Group Examples Clinical use
Nitroimidazoles Chloroquine Prophylaxis & treatment of malaria
Mefloquine Prophylaxis & treatment of malaria
Primaquine Treatment P.ovale, P. vivax
Quinine Treatment of P. falciparum
Biguanides Proguanil Prophylactic antimalarial
Miscellaneous Atovaquone Treatment of P. falciparum
Halofantrine Treatment of P. falciparum
Pyrimethamine Prophylaxis & treatment of
P. falciparum
Sulfadoxine Treatment of P. falciparum
Dapsone Prophylaxis of P. falciparum
Doxycycline Treatment of P. falciparum
Artemesin Treatment of malaria
 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