ANTHELMINTICS F A R M A K O L O G I 2

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ANTHELMINTICS

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ANTHELMINTICS

Anthelmintics →

• obat yang dapat mengeluarkan cacing dari saluran GI → Vermifuge (expel)

• membasmi cacing dewasa secara sistemik maupun yang menyerang organ atau jaringan → Vermicide (kill)

Afinitas terhadap cacing tinggi, toks thd inang rendah

Pada tubuh inang hidup di:

• GIT

• Jaringan (larva migrasi)

Merugikan inang:

• Menghabiskan makanan • Kehilangan darah

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Cacing Patogen (Metazoa)

• Intestinal nematodes (Ascariasis, Hookworms, Trichuriasis, Enterobiasis, Trichinosis, Strongyloidiasis) • Blood and tissue nematodes

(Filariasis: W. bancrofti, B.

malayi, O. volvulus,)

Nematodes (roundworms)

• Blood fluke (Schistosomes: S.

mansoni, S. japonicum, S.haematobium, S. mekongi)

• Lung and liver flukes

(Paragonimus spp, Clonorchis

sinensis, Opisthorchis spp, Fasciola hepatica)

Trematodes (flukes)

• Taeniasis (Taenia solium→

neurocysticercosis, T. saginata) • Diphyllobothriasis (Diphyllobothrium latum) • Hymenolepiasis (Hymenolepis nana) • Echinococcosis (Echinococcus granulosus) Cestodes (flatworms and tapeworms)

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Albendazol

❑

Benzimidazole carbamate

❑

Spektrum luas

❑

Absorbsi meningkat karna makanan berlemak

❑

Dimetabolisme menjadi aktif → albendazole sulfoksida

❑

Parasit Intraluminal → perut kosong

❑

Parasit jaringan → makanan berlemak

❑MK:

❑menghambat sintesis mikrotubul nematoda

❑larvicidal : hydated disease, cysticercosis, ascariasis,

hookworm

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Penggunaan Klinis Albendazol

Ascariasis , trichuriasis, hookworm, pinworm inf. • Dew,an>2th: SD 400mg • Ulang 2-3 h(asc) • 2w (pin) Hydatid disease (Echinococcosis) • Aktif thd E.granulosus • 400mg BD (dg mkn), 1m neurocysticercosis • +kortikosteroid • Symptomatic parenchymal or intraventicular cysts

(6)

Mebendazol

❑Absorbsi meningkat dengan makanan berlemak

❑Afinitas terhadap tubulin mamalia→ embryotoxic

→ KI ibu hamil

❑MK:

❑ blok uptake glukosa → penurunan cadangan glikogen ❑ Bekerja pada protein “ß tubulin” microtubular parasit→ menghambat polimerisasi → penurunan pembentukan mikrotubul.

❑ Mikrotubul penting untuk perkembangan larva, transport

karbohidrat, dan fungsi enzim, maintain the parasite tegument

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Mebendazol

❑Pharmacokinetics:

❑Absorpsi di GIT minimal (2-10%) → sangat efektif utk parasit di usus

❑75-90% oral dose → feses

❑t1/2 plasma : 1 h

❑

ES:

❑Keluar askaris lewat mulut dan hidung → parasit lapar dan mati perlahan

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Penggunaan klinis Mebendazol

❑Enterobiasis:

❑100mg single dose, repeated after 2-3 weeks → to kill the ova that have develop later.

❑Strict hygienic measures and simultaneous treatment of all children in the family or class is advocated to cut down autoinfection and person to person infection

❑ Tapeworms:

❑200 mg BD for 4 consecutive days (less effective)

❑Trichinella spiralis:

❑200 mg BD for 4 days; less effective than albendazole

❑Hydatid disease

❑200-400 mg BD or TDS for 3-4 weeks; less effective than albendazole ❖ ❖ 100mg chewable tab., 100mg/5mL susp.

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Thiabendazole

❑Aktif terhadap: round worm, hook worm, enterobius, trichuris, strongyloides and Trichinella spiralis.

❑Inhibit pertumbuhan telur dan larva, larva yang bermigrasi ke otot (T. Spiralis)

❑MK=mebendazol

❑Thiabendazole memiliki efek antiinflammatory, analgesic dan antipyretic → ineffective in filariasis

❑Pharmacokinetics

❑Cepat diabsorbsi, dimetabolisme melalui hidroksilasi dan konjugasi menjadi metabolit inaktif dan di ekskresi melalui urin

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Thiabendazole

❑

Dosis

❑25 mg/kg/day in two divided doses taken after meals.

❑Tablet must be chewed

→ 0.5 g/tab.; 0.5g/5mL susp. (30 mL bottle)

❑ it used as alternative to albendazole for:

❑ Strongyloidiosis

❑Cutaneous larva migrans

❑ Trichinosis – intestinal infestation

and larvae in muscles

Give a 2 days course.

If inadequate, repeat after a gap of 2 days

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Thiabendazole

❑

Efek samping:

❑Mual, muntah, hilang nafsu makan, sakit kepala

❑Hindari mengendarai kendaraan

❑Gatal, sakit perut, diare

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Diethylcarbamazine Citrate

❑ Obat pilihan untuk filariasis, loiasis, tropical eosinophilia

❑ Diberikan setelah makan

❑ Clinical uses: w.Bancrofti, B.malayi, B.timori, loa loa

❑ Loa:2w, inisial low dose (+antihistamin/kortiko) u/alergi

❑ 50mgx1 (H-1), 50mgx3(H-2), 100mgx3(H-3), 2mg/kgx3/d~2-3w

❑ Kemoprofilaksis: 300mg/w (loa), 50mg/m(bancrofti,malayan filariasis)

❑MK: immobilizes microfilariae dan merubah struktur

permukaan→ lepas dr jaringan

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Ivermectin

❑ Obat pilihan untuk Strongyloidiasis, onchocerciasis (mikorfilaria)

❑ Obat alternatif utk W. bancrofti, B. malayi, Ascariasis, Enterobiasis,

and trichuriasis. (SD)

❑ MK: nematodes → tonic paralysis → potensisasi transmisi GABAergic pada cacing → melalui Cl- _channel

❑Tidak dapat mempengaruhi cestodes and trematodes

❑ afinitas rendah terhadap reseptor GABA mamalia dan tidak dapat melewati blood-brain barrier (BBB)

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Penggunaan klinis invermectin

Onchocerciasis • SD 150µg/kg pada perut kosong • Dosis berulang (setiap 6-12bln) • terapi 1 + kortikosteroid → mikrofilaria kornea Strongyloidiasis • BD 200µg/kg • Immunocompromised → dosis berulang/bulan lain2 • B.malayi • Mansonella ozzardi ❑ES

❑Gatal, bengkak pada muka dan kaki

❑The Mazzoti reaction → respon imun terhadap antigen dari mikrofilaria

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Piperazine

•

1950→ ascariasis ,enterobiasis→ 100% cure rates; now,

second choice drug even for these worms

•

MK:

• Blok transmisi neuromuskular melalui kerja antagonis ACh → hiperpolarisasi → flaccid paralysis → cacing terlepas , hidup

• Afinitas terhadap reseptor kolinergik manusia <<

•

Pharmacokinetics

• Oral→ absorbed, partially metabolized in liver and excreted in urine.

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Piperazine

• ES:

• Safe and well tolerated

• Mual muntah , tidak nyaman perut, gatal

• Pusing

• Dosis toksik : kejang, kematian

• KI pada gagal ginjal dan epilepsi, aman pada ibu hamil

Penggunaan Klinis

Round worm: 4.5 g once a day for 2 cons. days; Children 0.75 g/year of age (max 4.5 g)

It can be used during pregnancy while other drugs cannot be used

Enterobiasis

50 mg/kg (max 2.5 g) once a day for 7 days or 75 mg/kg (max 4.5 g) single dose, repeated after 3 weeks

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Pyrantel Pamoate

• Introduced in 1969, high efficacy against Ascariasis, Enterobiasis and Ancylostomiasis

• Less active against Strongyloidiasis and inactive against Trichuris and other worms

•

Mekanisme kerja

• Aktivasi reseptor nikotinik kolinergik cacing→ depolarisasi persisten → spastic paralysis.

• Toksisitas selektif → afinitas >> reseptor cacing

• Antagonis piperazine

(piperazine → hyperpolarization, flaccid paralysis)

• Only 10-15% of an oral dose is absorbed, this is partly metabolized and excreted in urine

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Pyrantel Pamoate

•

ES:

• Jarang efek samping

• Sakit kepala (jarang)

• nonirritant

•

Penggunaan klinis:

• Ascariasis, Ancylostomiasis and Enterobiasis:

• A single dose of 10-15 mg/kg (max 1 g)

• A 3 days course for Necatoriasis and for Strongyloidiasis

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Praziquantel

•

Aktivitas terhadap schistosomes, other trematodes,

cestodes and their larval forms, cysticercosis

MK:

•

menyebabkan keluarnya kalsium intraselular → kontraksi

dan paralisis →cacing terlepas dari dinding saluran cerna

❖ Tabs should be swallowed whole with some liquid during meals.

Keeping tabs in mouth may release bitter taste that can produce nausea or vomiting.

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Praziquantel

• Pharmacokinetics

• Absorbsi cepat di GIT

• Phenytoin, Carbamazepin, and possibly dexamethazone →induksi metabolisme praziquantel→ menurunkan bioavailability

• melewati BBB

• T1/2 (1.5 h)

• Metabolit diekskresi lewat urin

• ES

• Rasa pahit (mual)

• Sakit perut, sakit kepala, pusing

• Utk infeksi schistosomes and visceral flukes → parasit yg mati menyebankan gatal, urtikaria, demam

Perhatian

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Penggunaan klinis Praziquantel

• Dosis dewasa = anak

- 50-100 mg/kg/d PO, 14 d

- pengobatan jangka panjang (bulan) →extraparenchymal infections

1. Tapeworms

- Single dose → cure rate 90-100%

- T. saginata, T. solium: 10 mg/kg single dose in the morning - H. nana, D. latum: 15-25 mg/kg single dose in the morning

in case of heavy infestation, re-treatment after 1 week

2. Neurocysticercosis

- 1st _{drug for neurocysticercosis: 50 mg/kg daily in 3 divided doses for 15}

days kills the larvae lodged in brain and other tissues.

Albendazole→ equally and more effective. Praziquantel and Albendazole are being used as first line base therapy

- also effective for dermal cysticercosis, but contraindicated in ocular cycticercosis

3. Scistosomes

- all three species can be treated with 40-75 mg/kg given once or in divided dose in one day.

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Nematoda

STH (soil transmitted helminths)→ ascariasis, trichuriasis, hookworm inf.

→ menyerang anak → BZAs

Ascaris lumbricoides

Terinfeksi melalu telur di makanan atau tanah

Obat: mebendazol(ringan), pyrantel pamoat (parah),

albendazol (piperazin jarang< ES neurotoksisitas,

alergi)

Terapi tambahan suplemen besi / transfusi darah

(23)

Nematoda

filarial→ LF (lymphatic filariasis)→ diethylcarbamazine+albendazol/

invermectin+albendazol → target kerja: tahap mikrofilarial yang bersikulasi di darah atau terbawa oleh vektor antropoda

Penyebab: Wuchereria bancrofti, brugia

spp.(sistem limfatik), mansonella spp (jaringan lain)

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Cestoda

Taenia saginata (cacing pita sapi)

Daging kurang matang Obat → praziquantel, _niclosamide

Taenia solium (caing pita babi)

Infeksi

Cacing dewasa di usus disebabkan oleh daging kurang matang dg

cysticerci

Cysticercosis → infeksi sistemik disebabkan larva → neurocysticercosis (meningitis,

epilepsi

Obat→ albendazol, praziquantel, kortikosteroid (inflamasi

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Trematoda

Schistosomiasis

S. Haematobium, S.

Mansoni, S.

Japonicum

Obat → praziquantel

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