ANTELMINTIK

Oleh : Faizal hermanto, S.Si., M.Si., Apt.

Out line Presentation Pendahuluan Pengelompokan Helmint Pengobatan infeksi cacing

- target kerja Antelmintik - obat antelmintik

introduction

Anthelmintics are drugs that either kill (vermicide) or expel (vermifuge) infesting heminths high affinity to the parasite, but lowest toxicity to the host

In the human body they live in: GIT,

Tissues or their larvae migrate into tissues

They harm the host by: depriving him food, causing blood loss, injury to organs, intestinal or lymphatic obstruction and

by secreting toxins4

Group of Helminth

3 Groups of HelminthHelminth

Nematodes (roundworms)

Trematodes (flukes)

Cestodes (flatworms and tapeworms)

Intestinal nematodes

Blood and tissue nematodes

Blood fluke

Lung and liver flukes

Nematodes (round worms) Nematode usus

Enterobius vermicularis (pinworm) Ascaris lumbricoides (roundworm) Trichuris trichiuria (whipworm) Hookworms Ancylostoma duodenale Necator americanus Strongyloides stercoralis (threadworm) Trichinella spiralis (cacing otot)7

Nematode darah dan

jaringan

Filariae

Wuchereria bancrofti. Obstruction of lymphatic vessels and elephantiasis. Filariasis. Brugia malayi Loa loa (inflammation of skin, eye) Onchocerca volvulus (ONCHOCERCIASIS or River blindness)8

Trematodes (flukes) Schistosoma species (blood fluke) S. mansoni S. japonicum S. haematobium Fasciolopsis buski(Intestinal fluke)

Fasciola hepatica (Sheep liver fluke) Clonorchis sinensis (Chinese liver fluke) Paragonimus westermani (Lung fluke)9

Cestodes (tape worms) Taenia saginata (beef tapeworm) Taenia solium (pig tapeworm)

Hymenolepis nana (dwarf tapeworm) Diphyllobothrium latum (fish tapeworm)

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Pengobatan infeksi cacing

Obat-Obat Untuk Pengobatan Infeksi CacingOrganisme yang menginfeksi Obat pilihan Cacing gelang (nematoda) Ascaris (gelang) Trichuris (cambuk) Necator (tambang) Strongyloides (benang) E. Vermicularis (peniti/kremi) Kombinasi infeksi ascaris, tricuris dan cacing tambang W. Brancofti (filariasis); B. Malayi (filariasis); Loa loa Onchocerca volvulus (onkosersiasis) Pir / Meb Meb Pir / Meb Tib / Ivr Meb / Pir Meb / Alb DEC Ivr

Obat alternatif

Pip, alb, atau Lev Alb atau Pir Alb atau Lev Alb atau Meb Alb Alb Ivr DEC + Suramin

Obat-Obat Untuk Pengobatan Infeksi CacingOrganisme yang menginfeksi Obat pilihan Cacing pipih (trematoda) Schistosoma Clonorchis sinensis (pada hati) Paragonimus westermani (pada paru) Fasciola hepatica (pada hati domba) Fasciolopsis buski (pada usus besar) Cacing pita (cestoda) T. Saginata ( pada sapi) T. Solum ( pada babi) Diphyllobothrium latum ( pada ikan) Hymenolepis nana (cacing pipih kecil) Pra Pra Pra Bitionol Pra / niklosmid

Obat alternatif

Metrifonat Oksamnikuin Meb / Alb Pra / emetin Tetrakloretilen

Nik / Pra Nik / Pra Nik / Pra Pra

Meb

Nik

Anthelmintics Target

Agonist acetylcholine Inhibitor cholinesterase Increase influx calcium

Neuromuscular transmission Agonist GABA muscle Nerve Work on chloride ion Neurotransmitter palsu channel Contoh: Piratel, piperazin, befenium, Energy Production Enzymes involved Substrate Contoh: Mebendazol, niclosamide, dll

Flacid paralisis Spastic paralisis

Benzimidazoles 1. Thiabendazole 2. Mebendazole 3. Albendazole

Tugas: cari struktur molekul

Broad spectrum agents. Bind to beta-tubulininhibit polymerization interfere with glucose uptake by the worm. Reduced ATP formation.

Mebendazol Merupakan benzimidazol sintetik yang mempunyai

aktivitas antelmintik spektrum luas MK : menghambat sintesis mikrotubulus nematoda mengganggu ambilan glukosa parasit mati atau diimobilisasi. Bekerja vermicid, larvacid dan ovicid. Farkin : penggunaan oral diabsorpsi sekitar 10 %, ekskresi lewat empedu dan urin.

Mebendazol KI : wanita hamil embriotoksik & teratogenik. ES : jarang terjadi dan berupa sakit perut & diare Penggunaan klinik :

- infeksi cacing kremi: 1 x 100 mg diulangi pada minggu ke 2 dan ke 4. - infeksi cacing gelang, tambang, benang, pita dan cambuk 2 dd 100 mg selama 3 hari bila perlu diulang setelah 3 minggu.

Tiabendazol Suatu benzimidazol sintetik MK :mengganggu agregasi mikrotubular melalui

penghambatan enzim fumarat reduktase. Bekerja larvacid dan ovicid. Farkin : resopsi cepat diusus, sebagian besar dikeluarkan melalui urin. KI : wanita hamil ES : mual, muntah, anoreksia, dan pising.

Tiabendazol Penggunaan

klinis : nematoda khususnya strongyloidiasis dan trichinosis serta larva migran pada kulit. Dosis 15 mg/Kg BB,2 dd 1 PC. Selama 2-4 hari.

Albendazol Antelmintik spektrum luas, memiliki keuntukan

karena penggunaannya single dose MK : menghambat ambilan glukosa oleh larva dan parasit stadium dewasa, mengurangi penyimpanan glikogen dan menurunkan pembentukan ATP. ES : gagngguan lambung-usus, alopesia, demam. KI : wanita hamil.

Albendazol Penggunaan klinik : Infeksi cacing askaris, kremi, tambang dan trikuriasis

dosis tunggal 400 mg. Strongiloidiasis 1 dd 400 mg dc. Selama 7-14 hari. Neurosistiserkosis : 15 mg/kg/hari selama 8 hari plus steroid. Cysticercosis of other tissues (muscle, subcutaneous area) also responds, but no drug should be given for ocular cysticercosis-blindness can occur due to the reaction.

Pirantel Pamoat Derivat

pirimidin yang merupakan antelmintik spektrum luas dan efektif pada pengobatan infeksi cacing kremi/peniti, askaris dan cacing tambang. Efektif terhadap cacing bentuk matur dan imatur tetapi tidak efektif untuk stadium migrasi dalam jaringan.

Pirantel Pamoat MK : Pyrantel activation worm nicotinic cholinergic receptors

persistent depolarization slow developing contracture and spastic paralysis

It has high affinity to the worm cholinergic

receptors (selective tox.). It has low affinity to the cholinergic receptors in mammalian skeletal muscle. It has an anticholinesterase action Antagonizes the action of piperazine (piperazine hyperpolarization, flaccid paralysis)

ES : gangguan saluran percernaan dan jarang sakit

kepala. KI : wanita hamil Pengguaan klinis : Infeksi cacing kremi dan gelang : dosis tunggal 2-3 tab @ 250 mg, anak-anak 10 mg/kgBB. Infeksi cacing cambuk : dosis tunggal 2-3 tab @ 250 mg selama 3 hari

Piperazine Introduced 1950, highly active against ascariasis and

enterobiasis 100% cure rates; now, second choice drug even for these worms Mechanism of action It blocks neuromuscular transmission in round worm by

antagonizing ACh action and causing hyperpolarization flaccid paralysis of the worm worms are expel alive and recover if placed in piperazine free medium. affinity for mammalian nicotinic cholinergic receptors selective tox.?

it does not affect neuromuscular transmission in man lack of

Pharmacokinetics Oral absorbed, partially metabolized in liver and excreted in urine. It metabolites: mononitroso form is carcinogenic25

Piperazine Adverse effects Safe and well tolerated Nausea, vomiting, abdominal discomfort and urticaria are occasional Dizziness and excitement occur at high doses Toxic doses: convulssion, death is due to respiratory failure Contraindicated in renal insufficiency and epileptics, but it safe in the pregnant Preparations As its hexahydrate, or salts like citrate, phosphate,

adepate, all are water soluble and tasteless26

DEC Uses

1. Filariasis: 2 mg/kg pc. produces rapid symptomatic relief; Mf disappear from blood

and patient become non infective to mosquitoes in 7 days; however, the adult worm survives in the lymphatics and gives rise to intermittent microfilaria and symptoms. Prolonged treatment with different schedules radical cure A total dose of 72-126 mg/kg spread over 12 days to several weeks satisfactory > 1 courses are needed with a gap of 3-4 weeks

Elephantiasis (chronic lymphatic obstruction) is not

affected by DEC27

DEC Uses Loa loa and O. volvulus: small doses 25-50 mg initially

Preparations50, 100 mg tab., 120mg/5mL syr., 50mg/5mL pediatric syr.; inj. 200mg DEC + CPZ maleate 5 mg and lignocaine 20mg in 10 mL vial

DEC Adverse effects Nausea, loss of appetide, headache, weakness and dizziness

are common but generally not serious.

A febrile reaction with rash, pruritus, enlargement of

lymph nodes and fall of BP may occurs due to mass destruction of Mf and adult worms mild to severe.

The reaction can be minimized by

starting with a low doses (0.5 mg/kg)

Given an antihistaminics and/or Corticosteroids

Leukocytosis and mild albuminuria are also noted The Mazzoti Reaction very common side effect and

may be fatal

IVERMECTIN Is an extremely potent semisynthetic derivative of the antinematodal

principle obtained from Streptomyces avermitilis.

Drug of choice for Onchocerciasis and strongyloidiasis Alternative drug for single dose treatment of W. bancrofti, B. malayi,

Ascariasis, Enterobiasis, and trichuriasis.

Effective in visceral larva migrans

Mechanism of action- nematodes tonic paralysis due to potentiation of GABAergic transmission in the worm Action through a special type of glutamate gate Cl- channel in the susceptible worms. * such channels are not involved in the motor control of cestodes and trematodes, they are unaffected by ivermectin - It has low affinity to mammalian GABA receptors and its inability to penetrate the blood-brain barrier

8. IVERMECTIN

A single 10-15 mg oral dose of ivermectin long lasting

reduction of Mf counts in onchocerciasis without affecting the adult worm. WHO: ivermectin replaced DEC for onchocerciasis (river blindness) control

programmed

Side effects: Mild: pruritus, giddiness and transients ECG changes Swelling of the face and lower limbs More important are reactions due to degradation product of

the Mf

The Mazzoti reaction an immune response to the antigens that are released from dead or dying microfilariae: papular rashes, severe itching, tachycardia and headache.

IVERMECTIN Semisynthetic analog of avermectin. Potent drug against human filaria infection, Oncocerciasis

(river blindness).

Could be used for W. bancrofti (elephantiasis). Not effective against cestodes and trematodes.

Intensifies GABA-mediated neurotransmission and causes

tonic paralysis of the musculature. invertebrates).

Opens glutamate-gated chloride channels (found only in

In humans, GABA is a neurotransmitter only in the CNS,

and Ivermectin does not cross the blood-brain barrier.

Selective toxicity.32

PRAZIQUANTEL Increases cell membrane Praziquantel (Biltricide)permeability in susceptible worms, resulting in loss of intracellular calcium, massive contractions, and paralysis of musculature. Also produces vacuolization and disintegration of schistosome tegument. This is followed by attachment of phagocytes to parasite and death. Tabs should be swallowed whole with some liquid during meals. Keeping tabs in mouth may release bitter taste that can produce nausea or vomiting.

PRAZIQUANTEL

Pharmacokinetics Rapidly absorbed from git and undergo first pass

metabolism in liver which limit its systemic bioavailability Phenytoin, Carbamazepin, and possibly dexamethazone

induce P metabolism reduce its bioavailability

It crosses BBB conc. in the brain and

CSF T1/2 is short (1.5 h) Metabolites are excreted chiefly in urine

PRAZIQUANTEL

Adult Dose- 50-100 mg/kg/d PO divided tid for 14 d (with cimetidine at 300 mg PO qid if patient also taking steroids or anticonvulsants)

- Longer courses (months) may be needed for extraparenchymal infections- Preliminary studies suggest alternative dosage regimen of 75 mg/kg given in single day (25 mg/kg q2h for total of 3 doses) may have similar efficacy Pediatric Dose Administer as in adults

PRAZIQUANTEL

Adverse effects despite systemic absorption no systemic toxicity. It tastes bitter can produce nausea others: abdominal pain, headache, dizziness and

sedation when used for schistosomes and visceral flukes

destroyed parasite produce symptoms like: itching, urticaria, rashes, fever, and bodyache No interaction with food, alcohol, or with tobacco

ContraindicationsDocumented hypersensitivity; ocular cysticercosis; NCC resulting in cerebral edema, uncorrected hydrocephalus, cysticerci near cerebral vessels, or ocular disease

11. PRAZIQUANTEL

Interactions

Significant first-pass metabolism when coadministered with corticosteroids, carbamazepine, phenytoin, or, probably, phenobarbital; levels decrease by approximately one half compared with praziquantel alone; cimetidine co-administration significantly inhibits metabolism and should be used to counterbalance effect of concurrent steroids or anticonvulsantsPregnancy - Usually safe but benefits must

outweigh the risks.

PRAZIQUANTEL

Precautions

Destruction of parasite within eyes can cause irreparable lesions (ocular cysticercosis should not be treated with praziquantel); Caution while driving or performing other tasks requiring alertness on day of and following treatment; Minimal increases in liver enzymes reported; When schistosomiasis or fluke infection associated with cerebral cysticercosis, hospitalize patient for duration of treatment

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PRAZIQUANTEL

Uses1. 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 individed dose in one day.

PRAZIQUANTEL Broad spectrum drug. Effective against schistosomes and cysticercosis. Human and animal trematodes, cestodes, and nematodes. Increases membrane permeability to calcium,

causing marked contraction initially and then paralysis of trematode muscles; followed by vacuolization and parasite death.

NICLOSAMIDE 1960 highly effective against cestodes: Taenia saginata, T.

solium, Diphyllobothrium latum and Hymenenolepis nana and thread worm

Mechanism of action- to act by inhibiting oxidative phosphorylation in mitochondria and interfering with anaerobic generation of ATP by the tape worm. - Injured by niclosamide, the tape worm are partly digested in the intestine.

- In case of T. solium, digested of dead segments can be hazardous, because the ova released from them develop into larvae in the intestine, penetrate its wall and cause visceral cysticercosis

NICLOSAMIDE Regimen for tape worm Niclosamide (0.5 g tab.) after light breakfast, 2 tablets

chewed, swallowed with water, followed by another 2 tablets after 1h (total 2g); Total dose for children 2-6 yrs is 1g A saline purge is given 2h after the later dose to wash off the

worm The scolex should be searched in the stools to be sure that

the worm will not grow again

NICLOSAMIDE Regimen for tape worm* For H. nana, the 2g dose is repeated daily for 5 days

needed because the cycticerci of H. nana (which are not affected by niclosamide) develop in jejunal villi of the same host and worm appear in the intestinal lumen after 4 days.However, no purgative is required.

Treatment may have to be repeated after 10 days

NICLOSAMIDE

Adverse effects Niclosamide is tasteless and non irritating Minimally absorbed from git no systemic tox. occurs. It is well tolerated minor abdominal symptoms Malaise, pruritus and light headache are rare. Safe during pregnancy and in patient with poor health