Anti Amuba Dan Anti Malaria
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ANTIPROTOZOA
dr Hany Yusmaini., MKesDepartemen Farmakologi dan Terapi
FK UPN Veteran Jakarta
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• Protozoa : eukariotik • Proses metabolisme menyerupai pejamu
Efek toksik pada pejamu
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OBAT ANTIPROTOZOA
• ANTI AMOEBIASIS
• ANTIMALARIA
• ANTITRIPANOSOMIASIS
• ANTIGIARDIASIS
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ANTI AMOEBIASIS
Amoebiasis : infeksi saluran cerna yang disebabkan oleh Entamoeba histolytica
Siklus hidup : 2 bentuk - Kista : dapat hidup diluar tubuh- Tropozoit : hidup di dlm tubuh, labil,
invasif
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Siklus hidup Entamoeba hystolityca
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Klinis : disentry ringan sampai dengan berat bab berdarah – lendir akut – kronis
Amubiasis sistemik : abses hati abses paru abses otak
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Sesuai tempat kerjanya antiamuba dibagi :
1. AMUBISID LUMINAL diloksanid furoat, paromomisin, tetrasiklin
2. AMUBISID SISTEMIK emetin, dihidroemetin, kloroquin
3. AMUBISID CAMPURANmetronidazol
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METRONIDAZOLE
Obat pilihan untuk
E hystolitica, Giardia lamblia, Trichomonas vaginalis
Kokkus anaerobBasil anaerob (bacteroides, clostridia)
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FARMAKOKINETIKA : peroral baikD : ke seluruh cairan dan jaringan tubuhM : interaksi dengan inducer dan inhibitor
enzim metabolisme di hatiE : urine
ESO : mual, muntah, nyeri epigastrium, kram perut, rasa logam, vertigo, parestesi
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AMUBISID LUMINAL
1. DILOKSANID FUROAT Indikasi : amubiasis intestinal Pemberian p.o ESO : ringan : flatulen, urtikaria, mulut kering
2. PAROMOMISIN Trmsk aminoglikosid Hampir tidak diabsorpsi
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Menurunkan populasi flora intestinalAmubisid langsung : efek pd membran sel
amubaESO : ggn sal cerna
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AMUBISID SISTEMIK
1. KLOROKUIN Antimalaria Digunakan jg sbg amubisid sistemik Mencegah abses hati amuba (bersama
metronidazol) Tidak bermanfaat untuk amubiasis
intestinal
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Obat Antimalaria
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MALARIA
Infeksi akut yang disebabkan oleh 4 spesies plasmodium.
- Plasmodium falciparum : malaria tropika- Plasmodium vivax- Plasmodium ovale- Plasmodium malariae : malariae kuartana
- Plasmodium knowlesi : primata
Malaria tersiana
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SIKLUS HIDUP PLASMODIUM
- Siklus aseksual : pada hospes antara : manusia- Erythrocytic cycle- Exoerythrocytic cycle
- Siklus seksual : pada hospes definitif : nyamuk anopheles- Sporogonic cycle
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Life cycle of the malarial parasite
Sporogeny (sexual)
Schizogony (asexual)
Man : Intermediate host
Mosquito : Definitive host
True causal prophylactics
Causal prophylactics
Supressives
Gametocidal
Sporonticide
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Tantangan terbesar : menurunnya efikasi obat2 anti malaria dan
masalah resistensi
Thn 2004 di Indonesia digunakan obat kombinasi ACTs : artesunat +
amodiaquin
SKRT 2001, dari 484 kab/kota 338 nya mrpkn daerah endemis
malaria, 15 juta kasus, 38rb kematian per tahun
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TERAPI MALARIA
PROFILAKSIS : klorokuin, hidroksiKlorokuin, meflokuin, primakuin, pirimetamin, doksisiklinPirimetamin + sulfadoksin, proguanil
TREATMENT : Klorokuin, hidroksiklorokuinMeflokuin, primakuin, pirimetamin, kininPirimetamin + sulfadoksin, proguanil, Artemisinin (ACT)
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OBAT ANTI MALARIA
1. Skizontosid Jaringan : Primakuin, Proguanil, 2. Skizontosid Darah : Klorokuin, Kuinin, Meflokuin,
Pirimetamin, artemisinin3. Sporontozid : Pirimetamin4. Gametositosid : Primakuin, Proguanil, Klorokuin, Kina
Skizontosid darah mengendalikan serangan klinikSkizontosid jaringan mencegah relaps..Kombinasi keduanya : pengobatan radikal
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SKIZONTOSID JARINGAN (LIVER STAGES) : Primakuin,
Proguanil SKIZONTOSID DARAH (BLOOD STAGES) :
Klorokuin, Kuinin, Meflokuin, Pirimetamin, Artemisinin
SPORONTOSID :Pirimetamin
GAMETOSITOSID :Primakuin Proguanil,
Klorokuin, Kina
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Tidak ada satu obat yang bekerja pada semua stages, complete elimination membutuhkan lebih dari satu obat
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KLOROKUIN
4-Aminoquinolin, drug of choice utk terapi dan profilaksis malaria sejak tahun 1940 an, Skrg resistensi meningkat
Skrg digunakan untuk infeksi plasmodium vivax, ovale dan falciparum (yang sensitif), lebih baik drpd kina
Efektif untuk fase eritrosit (skizontosid darah), tidak efektif untuk fase eksoeritrosit (liver stage)
Untuk P vivax : perlu kombinasi dengan primakuin untuk mencegah relaps
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Chloroquine: – Synthesized by Germans in 1934 ( resochin)
– d & l isomers, d isomer is less toxic – Cl at position 7 confers maximal antimalarial
efficacy
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Mekanisme kerja : - menghambat aktivitas polimerase heme plasmodia yang merubah heme (toksik) menjadi hemozoin (non toksik)- mempengaruhi sintesis DNA plasmodium
Resistensi >>> t.u terhadap plasmodium falciparum
Warning G6PD : hemolisis
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Hemoglobin Globin utilized by malarial parasite
Heme (highly toxic for malaria
parasite)Chloroquine Quinine, (-) (+) Heme Polymerase
mefloquine Hemozoin (Not toxic to plasmodium)
Mechanism of action
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Pharmacological Actions1. Antimalarial activity:
– High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum
– Gametocytes of vivax– No activity against tissue schizonts – Resistance develops due to efflux mechanism
2. Other parasitic infections: – Giardiasis, taeniasis, extrainstestinal
amoebiasis 3. Other actions:
– Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory, antihistaminic , local anaesthetic
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Pharmacokinetics
• Well absorbed, tmax 2-3 hrs , 60 % protein bound
• Concentrated in liver , spleen, kidney, lungs , leucocytes
• Selective accumulation in retina: occular toxicity
• T1/2 = 3-10 days increases from few days to weeks
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Adverse drug reactions
• Intolerance: – Nausea, vomiting, anorexia – skin rashes, angioneurotic edema,
photosensitivity, pigmentation, exfoliative dermatititis
– Long term therapy may cause bleaching of hair
– Rarely thrombocytopenia, agranulocytosis, pancytopenia
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Adverse drug reactions• Occular toxicity: High dose prolonged therapy
– Temporary loss of accommodation – Lenticular opacities, subcapsular cataract – Retinopathy: constriction of arteries, edema, blue
black pigmentation , constricted field of vision. • CNS:
– Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity
• CVS: – ST & T wave abnormalities, abrupt fall in BP
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Dosage
Dosis awal 10 mg/kg BB dilanjutkan 5 mg/kg BB pada 6, 12, 24 dan 36 jam berikutnya sehingga tercapai dosis total 30 mg/kgBB dalam 2 hari
Posologi :
Tablet p.o klorokuin fosfat 500 mg dan 250 mg dan syrup klorokuin fosfat 50mg/5ml
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• Tahun 1973 pertama kali ditemukan kasus resisten p falciparum thd klorokuin di Indonesia (Kalimantan Timur)
• Tahun 1990, dilaporkan telah tjd resistensi P falciparum thd klorokuin dan fansidar (P-S) di seluruh provinsi di Indonesia
2001 : WHO merekomendasikan penggunaan ACT (Artemisinin based Combination Therapy) : sbg first line therapy menggantikan klorokuinObat kombinasi : artesunat + amodiakuin
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Drugs used in chloroquine resistant malaria
• Mefloquine
• Quinine
• Sulfadoxine pyrimethamine
• ACT
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Di Indonesia ada 2 regimen ACT
1. Artesunate + amodiakuin2. Dihydroartemisinin + piperakuin
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KININ DAN KUINIDIN• Berasal dari kulit pohon cinchona , obat tradisional org Indian• Abad ke -18 alkaloid cinchona diekstraksi , dan sejak itu digunakan
untuk profilaksis dan treatment malaria• Skizontosid darah semua plasmodium, gametositosid P vivax dan P
ovale• Kurang efektif dibandingkan klorokuin, dan lebih toksik• Rapid onset, t1/2 lama
• Kuinidin adalah dekstro isomer dari Kinin, sama efektif dengan Kinin• t1/2 lebih cepat• Indikasi : treatment severe infection plasmodium falciparum
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KININ DAN KUINIDIN
ESO : - dosis terapi mybbkan tinitus, headache, nausea, dizzines, flushing, visual disturbance Cinchonism
- Black Water Fever : hemolisis, hemoglobinuria krn reaksi hipersensitivitas
Indikasi : Severe Infection by Plasmodium Falciparum Tidak digunakan untuk profilaksis
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PIRIMETAMIN
- Skizontosid darah kerja lambat dengan waktu paruh lebih lama
- Sering dikombinasi dengan sulfadoksin
(fansidar) : efek sinergis
- Mekanisme kerja : menghambat dihidrofolat reduktase
- ESO : anemia makrositik akibat def asam folat, trombositopenia, agranulositosis
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Sulfadoxine-pyrimethamine
• Fansidar• Sulfadoxine 500 mg + pyrimethamine 25
mg, 3 tablets once for acute attack • Not recommended for prophylaxis• Use:
– single dose treatment of uncomplicated chloroquine resistant falciparum malaria
– patients intolerant to chloroquine– First choice treatment for toxoplasmosis
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PRIMAKUIN
• Skizontosid jaringan
• Mengeradikasi bentuk laten dari plasmodium vivax dan ovale
• Tidak efektif untuk fase eritrositer
• Mencegah relaps
• Biasanya dikombinasi dengan klorokuin
• ESO : anemia hemolitik pada G6PD : ras asia, mediterania >> ras afrika
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AMODIAKUIN
• Antimalaria derivat 4-aminokuinolin
• Efektifitasnya sama dengan klorokuin thd p. falciparum yg sensitif thd klorokuin dan efektif untuk strain yg resisten klorokuin
• Tidak untuk profilaksis ; efek samping agranulositosis
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• Absorpsi peroral baik• Metabolisme di hati : konversi menjadi
metabolit aktif (desetilamodiakuin) mempunyai efek terapi lebih besar dari parent drugnya
• Mekanisme kerja : menghambat polimerisasi haem yg bersifat toksik pd plasmodium
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ARTEMISININ & derivatives
- Sesquiterpen lacton endoperoxide berasal dari tanaman obat : Qing Hao (Artemisia annua), dikenal dlm pengobatan cina > 2000thn yg lalu, thn 1596 digunakan utk malaria, 1972 diidentifikasi senyawa aktifnya : Qing haosu : Artemisinin
- Skizontosid darah yg poten, alternatif pilihan untuk malaria tropika yg berat yg resisten thd obat lainnya
- Very potent, low toxic and fast acting anti malaria
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PLANT- ARTEMISIA ANNUA
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Artemisinin derivatives
• Artesunate
• Artemether
• Arteether
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Mekanisme Kerja : menghambat Ca-ATP ase di retikulum sarcoplasmik plasmodium falciparum
Indikasi : - infeksi p falciparum resisten-klorokuin - treatment of severe p falciparum - MDR malaria
Efektifitas Terapi meningkat bila dikombinasi dengan antimalaria lainnya
Biasanya dikombinasi dengan amodiakuin, doksisiklin, meflokuin (mencegah relaps)
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ACTs
Dosis sebaiknya berdasarkan berat badan Artesunat 4 mg/kgBBAmodiakuin 10 mg/kgBBPrimakuin 0,75 mg/kg BB
Bila tidak dapat dilakukan perhitungan BB, dapat menggunakan tabel berdasarkan umur sbb
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Why combination therapy
• rapid clinical & parasitological cure
• high cure rates and low relapse rates
• absence of resistance
• good tolerability profile
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PROFILAKSIS MALARIA
Kemoprofilaksis penting dilakukan pada org sehat yg akan memasuki wilayah endemis malaria
Perhatikan pola kepekaan parasit terhadap antimalaria
Peningkatan dosis : meningkatkan risiko ESO
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Cara pemberian :
- 2 minggu sblm masuk daerah endemis sampai dengan 4 minggu setelahnya
- 1 hari sebelum masuk daerah endemis sampai dengan 1 minggu
meninggalkan daerah endemis
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Practice points
• Most antimalarials are bitter in taste give along with milk or fruit juice
• If vomiting occurs within hour of drug repeat full dose, in case of mefloquine repeat half dose
• If vomiting after 1 hour no need to repeat
• Postural hypotension : quinine, chloroquine