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 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



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

Anthelminthics

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



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)




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)


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

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

Antiprotozoa

Classification of antiprotozoals


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. histolytica

as follows:

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


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.


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


Leshmaniasis :

• Antimonials - Sodium stibogluconate

• Pentamidine

• Amphotericin• Amphotericin


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


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


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



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

tmd175 slide pharmacology of antifungi - anthelminthics - antiprotozoal

Documents

cell membranefungi

fluconazole urine3

fluconazole muntah

fluconazole tablet

antifungal therapy

flucytosine mual

salicylic acid

nystatin fungalsterol