ANTIVIRAL ANTI FUNGAL ANTIPROTOZOAL ANTIHELMINTHICS SULANTO SALEH-DANU R., dr., SpFK Clinical Pharmacology Division, Pharmacology & Therapy Departement, FACULTY of MEDICINE, MEDICI NE, UNIVERSIT UNIVERSI TAS GADJAH MADA 1
VIRUS
BAKTERI JAMUR
INFEKSI
dll
SISTEM BIOLOGI TUBUH MANUSIA
SIMPTOM & SIGN PATOLOGIS
TUMBUH dan BERBIAK 2
OBAT OBA T- OBA OBAT T ANT ANTIIN IINFEK FEKSI SI
Obat-obat ObatAntiviral
ObatObat-obat Antibakterial
ObatObat-obat Antifungal ObatObat-obat Antiprotozoal ObatObat-obat Anthelmintik 3
KLASSIFIKASI ANTIINFEKSI 1. BE BERD RDAS ASAR ARKA KAN N JE JENI NIS S MI MIKR KROO OORG RGAN ANIS ISME ME : ANTIVIRAL ANTIBAKTERIAL ANTIFUNGAL ANTIPROTOZOA ANTIPARASIT ANTHELMINTHIK 2. BE BERD RDAS ASAR ARKA KAN N SIF SIFAT TERH TERHAD ADAP AP BA BAKT KTER ERII : - BAKTERIOSID - BAKTERIOSTATIK 3. BER BERASA ASARKA RKAN N PADA PADA SPE SPEKTR KTRUM UM ANT ANTII MIKR MIKRORG ORGANI ANISME SME : SPECTR UM ( berspektrum luas ) - BR OAD SPECTRUM SPECTR UM ( berspektrum sempit ) - NA RROW SPECTRUM 4.
BERDASARKAN STRUKTUR / GUGUS KIMIA KIMIAWI. WI. 4
EFFICACY SAFETY
TREATMENT
COSTLY SELECTION OF MEDICINES
PHARMACOTHERAPEUTICS
ROUTE
OF ADMINISTRATION
DOSAGE
FORM
FREQUENY
NON PHARMACO- THERAPIES
DURATION ADVERSE
DRUG REACTION
INTERACTION
5
DRUG DOSAGE, ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION
PHARMACOKINETIC
PHARMACOTHERAPY
PHARMACODYNAMIC
TROPIC- COUNTRIES SITUATION BODYWEIGHT NUTRIONAL STATUS & DIETARY HABITS TROPICAL ENVIRONMENT: ENVIRONMENT: climatic factors infections and infestations environment environment pollutants (chemicals, mycotoxins, alcoholism, smoking, etc)
EFFECTS, RESPONSES, INTERACTIONS, ADVERSE EFFECTS, Etc., etc. 6
AREA-CLIMATE
ABNORMLITY BY
CAUSATIVE CAUSATIVE AGENTS AGE NTS
GENETIC
PARASITES
DEGENERATIVE
FUNGAL
ARTIC/ANTARTIC
4-SEASON COUNTRIES
diseases
SUBTROPIC
TROPIC
METABOLISM
MALIGNANCY
BACTERIAL
VIRAL
OTHERS INFECTION 7
OBA OBAT-OBA -OBAT T ANTI ANTIVI VIRA RAL L parasite/mikroorganisme yang hidup parasite/mikroorganisme intraseluler host berkembang dengan replikasi didalam sel (host) hidup metabolisme virus sangat mirip dengan metabolisme dengan metabolisme sel host sehingga sulit untuk mendapatkan obat antiviral yg selektif dan aman.
8
ACRONYMS & OTHER NAMES (pada virologi) 3TC AZT CMV CYP d4T ddC ddL EBV FTC HAART HBV HBC HHV-6 HIV HPV HSV IFN KSHV NNRTI NRTI PI RSV SVR VZV
Lamivudine Zidovudine (previously azido-thymidine) Cytomegalovirus Cytochrome P450 (enzym) Stavudine Zalcitabine Didanosine Epstein-Barr virus Emtricitabine Highly active antiretroviral therapy (aksi/potensi) Hepatitis B virus Hepatitis C virus Human herpesvirus-6 Human immunodeficiency virus Human papillomavirus Herpes simplex virus Interferon -associated herpesvirus Kaposi’s sarcoma sarcoma-associated Nonnucleoside reverse transcriptase inhibitor (aksi) Nucleoside reverse transcriptase inhibitor (aksi) Protease inhibitor (aksi/site of action) Respiratory syncytial virus Sustained antiviral response (response) Varicella-zoster virus 9
VIRAL REPLICATI REPLICATION ON & SI SITE TE OF A NTI NTIVI VIRAL RAL DRUG A CTI CTION ON
1.Viral attachment & entry 2.penetration 2. penetration
Blocked by envuvirtide (HIV) maraviroc (HIV) docosanol (HSV) palivizumab (RSV)
3.uncoating 3. uncoating 4.early protein synthesis 5.nucleic 5. nucleic acid synthesis
SEL MAMMALIA
6.late protein 6.late synthesis & processing
8. Viral release
( Safri n,S.,2009 )
Blocked by neuroaminidase inhibitors (influenza)
7.packing & 7.packing assembly
Blocked by interferon-alfa (HBV, HCV) Blocked by amantadine, rimantadine (Influenza-A)
Blocked by NRTIs(HIV), NNRTIs (HIV), acyclovir (HSV), foscamet (CMV), entecavir (HBV)
Blocked by protease inhibitors (HIV) 10
OBAT OBAT-OBAT -OBAT ANTIRETROVIR ANTIRETROVIRAL AL NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR ( NRTI ):
N0NNUCLEOSIDE ( NNRTI ) :
-Abacavir -Didanosine -Emtricitabine -Lamivudine -Stavudine -Tenofovir -Zalcitabine -Zidovudine
-delavirdine -etravirine -efavirens -nevirapine
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PROTEASE INHIBITORS ( PI ) :
Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/Ritonavir Nelfinavir Saquinavir Tripanavir
FUSION INHIBITORS : enfuvirtide CCR5 receptor antagonists : maraviroc
INTEGRASE INHIBITORS : raltegravir
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OBAT-OBAT UNTUK FARMAKOTERAPI DAN PREVENTIF terhadap :
INFEKSI HERPES SIMPLEX VIRUS ( HSV ) dan VARICELLA-ZOSTER VIRUS (VZV). ACYCLOVIR
(po (po;; iv iv & & topical) *) FAMCICLOVIR (po (po)) *) FOSCARNET (iv (iv)) *) DOCOSANOL (topical) PENCICLOVIR (topical) TRIFLURIDINE (topical) VALACYCLOVIR (po (po)) *) *) = hati-hati pada penderita gangguan fungsi ginjal
13
Acyclovir Penciclovir Ganciclovir
Virus-specified enzymes
monophosphate (eg, thymidine kinase, UL97)
Host kinases
diphosphate
Trifluridine Cidofovir fasconet
triphosphate
Incorporation into viral DNA
Chain termination
MECHANISM of action of antiherpes agent
Competitive inhibition of viral DNA polymerase Inhibition of viral DNA synthesis 14
OBAT-OBAT UNTUK FARMAKOTERAPI INFEKSI CYTOMEGALOVIRUS
( CMV )
CIDOFOVIR (iv) CMV retinitis FOSCARNET (iv) CMV retinitis GANCICLOVIR (iv) CMV retinitis (po) CMV prophylaxis (intraocular implant) CMV retinitis VALGANCICLOVIR (po) CMV retinitis CMV prophylaxis (pasien prophylaxis (pasien transplantasi)
*) = dosis harus dikurangi pada pasien dengan gangguan ginjal
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OBAT-OBAT ANTIHEPATITIS HEPATITIS B : -Lamivudine
-Adefovir dipivoxil -Entecavir -Interferon alfa-2b
HEPATITIS C:
DOSIS HARUS HITUNG DENGAN TELITI PADA PASIEN DENGAN INSUFFISIENSI RENAL
Pegylated interferon alfa-2a Pegylated interferon alfa-2b Ribavirin *) Interferon alfa-2a Interferon alfa-2b Interferon alfa-2con
*) = *) = TIDAK DIREKOMENDASI UTK MONOTERA M ONOTERAPI PI
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OBAT OBAT ANTI-INFLUEN ANTI-INFLUENZA ZA -Amantadine & Rimantadine -Zanamivir & Oseltami
OBAT OBAT ANTIVIRAL ANTIVIRAL lainnya lainnya Interferon-interferon Ribavirin Palivizumab imiquimod
Catatan : detail farmakokinetik-farmakodinamik; farmakokinetik-farmakodinamik; dosis; dan ADR IC & C L I NI NIC A L P H A R M A C O L O G Y lihat : Sharon Safrin in B A S IC B erttram G. Katzung ; 11th 11th Ed . 2009 2009,, pg 845 – 875. 17
CATATAN UNTUK ANTIVIRAL 1. OBAT OBAT-OBAT -OBAT YANG YANG TERCANTUM DIAT DIATAS BEBERAPA BEBERAPA BELUM BEREDAR DIPASARAN INDONESIA dan MASIH DALAM E A R L Y MA DAN INVESTIGASI M A R K E T DAN 2. VIRUS VIRUS HIDUP HIDUP HANY HANYA DIDALAM SEL HOST 3. BAHWA BERBIAKNYA VIRUS (REPLIKASI) (REPLIKASI ) SANGAT SANGAT TERGANTUNG PADA PROSES SINTETIK SEL HOST 4. OBAT-OBAT OBAT-OBAT ANTIVIRA ANTI VIRAL L BISA DIKATAKAN DIKATAKAN EFEKTIF EFEK TIF BILA MASUK- KELUARNYA VIRUS PADA SEL HOST MEMBLOCK MASUK-KELUARNYA atau AKTIF DIDALAM DIDAL AM SEL HOST HOS T (TANP (TANPA A MENGGANGGU KEHIDUPAN SEL HOST) 5. PENGO PENGOBA BAT TAN MEMBUTU MEMBUTUHKA HKAN N WAKTU LAMA PERLU SELALU WASPADA WASPADA TERHADAP A DVERSE DRUG REACTION 18
ANTIFUNGAL
SYSTEMIC (infection) DRUGS (oral / parentral)
MUCOCUTANEUS INFECTION (ORAL)
MUCOCUTANEUS INFECTION (TOPICAL)
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PROBLEMATIK PROBLEMATIK INFEKSI FUNGAL / JAMUR : - JUMLAK KASUS MENINGKAT - MUNCULNY MUNCULN YA JAMUR RESISTEN terhadap ANTIFUNGAL - DIJUMPAI : organ transplantation transpl antation bone marrow transplantation endemic HIV PEMAKAIAN ANTIMIKROBA SPEKTRUM LUAS pada pasiem kritis (superinfeksi).
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AMPHOTERICIN B AZOLES : Ketonazole Itranazole Fluconazole Voriconazole Posaconazole
ANTIFUNGAL
ECHINOCANDINS: Caspofungin Micafungin Anidulafungin
OTHERS : Griseofulvin Terbinafine (allylamine) TOPICAL : Nystatin Azoles Allylamine 21
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AMPHOTERICIN B
Merupakan amphoteric polyene macrolide Nyaris tidak larut dalam air Preparat dalam bentuk suspensi koloidal (pemakaian sistemik)
MEKANISME KERJA : - fungisidal selektif - dinding membran sel fungi mengandung ergosterol (predeominan :cholesterol) - terikat pada ergosterol mempengaruhi permeabilitas sel membran., kerusakan : gangguan intraseluler ion dan macromolekul berakibat kematian sel fungi. SPEKTRUM ANTIFUNGAL : - luas Candida albicans Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Aspargillus fumigatus , dll 23
PENGGUNAAN DI KLINIS : - Digunakan pada penyelamatan jiwa karena infeksi jamur. jamur. INITIAL INDU CTION dilanjutkan dengan AZOLE - INITIAL (severe fungal pneumonia; severe cryptococcal meningitis; dan pada penyebaran endemik mycoses ) - Pemberian Pemberian : IV /infus /infus (pelan-pelan (pelan-pelan : 0,5-1 mg/kg/d) total 1-2 g. - Intrathecal kadang-kadang juga diberikan untuk fungal meningitis - intraarticular utk fungal arthritis - irigasi kandung kemih : candiduria. - Juga diberikan secara topical hasil muaskan.
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A DVERS DVERSE E DRUG REA CTI CTION ON / A DR MMEDIAT ATE E REACTION (infu sio n-rela n-related ted tox icity ) -I MMEDI demam; mengigil; muscle spasms; vomiting; headache; hypotensi. Dapat dicegah : memperlambat infus / menurunkan dosis harian atau dengan test 1mg iv Premedikasi : antipyretik; antihistamin; meperidine atau kortikosteroid . -CUMUL ATIVE TOXICITY TOXICITY :► Kerusakan ginjal.
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AZOLES SENYAWA SENYAWA SINTETIK SINTE TIK : imidazole triazole
R
X =C X =N
N X N
Pharmacologic propertes of AZOLE drugs Water Wat er sol.
Absorp.
CSF : srm conc.rat
t½ (hours)
Elimination
Formulation
Ketoconaz Ketoconaz
low
variable
< 0.1
7 – 10
hepatic
oral
Itraconaz
low
variable
< 0.01
24 – 42
hepatic
oral; i.v. i.v.
Fluconaz
high
high
> 0.7
22 – 31
renal
oral; i.v. i.v.
Voriconaz
high
high
--
6
hepatic
oral; i.v. i.v.
Posaconaz
low
high
--
25
hepatic
oral 26
MECHANISM O F ACTION ACTI ON
-REDUCTION OF ERGOSTEROL SYNTHESIS by INHIBITION OF FUNGAL
CYTOCHROME CYTOCHROM E P-450 ENZYMES SIFAT SELEKTIF : pada fungal affinitas CYTOCHROME-450 > manusia IMIDAZOLE selektifitas < TRIAZOLE TRIAZOLE
INTERAKSI OBAT Pada METABOLISME 27
INTERAKSI OBAT Pada METABOLISME
ITRACONAZOLE ITRACONAZOLE + RIFAMPICINS (RIFAMPIN,RIFABUTIN,RIFAPENTINE) ►
BIOAV BIOAVAILABILITY AILAB ILITY ITRACONASOLE ITRACONA SOLE berkurang.
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ANTI FUNGAL ANTIPROTOZOAL ANTIHELMINTHICS
Reference: KATZUNG,BG., (ed.) 2009, BASIC AND CLINICAL PHARMACOLOGY , 11TH Ed., pg : 835-844; 899-922; 923-934 Lange-McGrawHill., Boston. 29
ANTIPROTOZOAL / anti parasitic MALARIA : plasmodium falciparum plasmodium vivax plasmodium malariae plasmodium ovale plasmodium knowlesi (kera) AMEBIASIS (entamoeba histolytica) histolytica) intestinal amebic colitis extraintestinal amebic
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IMMUNIZATION
MICROORGANISM / PARASIT, dll
PREVENTIVE
INVASIVE
KILLED & DESTROYED”
HOST
SAFE “
PHARMACOTHERAPY PHARMACOTHERAPY should be : 31
1.
UNIQUE EN ENZYMES
-Enzymes for dihydropteroate syntesis
Apicomplexa
Sulfones and Sulfonamides
-Glycolipid synthesis
African trypanosmes
None
-Pyruvate:ferrodoxin oxidoreductase
Anaerobic protozoa
Nitroimidazole
-Pyruvate phosphate kinase
Anaerobic protozoa
None
-Nucleoside phosphotranferase
Flagellated protozoa
Allopurinol riboside and formycine B
-Trypanothione reductase and peroxidase
Kinetoplastida
Nifurtimox
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2. INDISPENSABLE ENZYMES
Lanosterol C-14α demethylase
Leishmania & Trypanosoma Trypanosoma cruzii
Azoles
Purine phosphoribocyl transferase
Protozoa
Allopurinol
Purine nucleoside kinase
Trichomonas Trichomonas vaginalis and Entamoeba hystolytica
None
Ornitine decarboxylase
African Trypanosomes
α
(S)-Adenosylmethionine decarboxylase
African trypanosomes
Diamidines
Glycolytic enzymes
Kineplastida
Glycerol plus salicylhydroxamic acid and suramine
-Difluoroethylornithine
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3. INDI INDISP SPEN ENSA SABL BLE E BIOC BIOCHE HEMI MICA CAL L FUNC FUNCTI TION ON WITH DIFFERENT PHARMACOLOGIC PROPERTIES
Dihydrofolate reductase-thymidylate synthase bifunctional enzyme
Apicomplexa and Kinetoplastida
Pyrimethamine
Thiamine transporter
Coccidia
Amprolium
Mitochondrial electron transporter
Apicomplexa
4-Hydroxyquinolines and 2-hydroxynaphthoquinones
Microtubules
Helminth
Benzimidazoles
Nervous synaptic transmission
Helminth and ectoparasite
Levamisole, piperazine, the milbemycins, and the avermectine
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1. MALARIA - The most important tropical disease, affecting over 2200 million, more than 2 million deaths/year . - Cause : PLASMODIUM : - P. VIVAX - P. OVALE - P. MALARIAE - P. FALCIPARUM severity deaths -COMPLICATION : 1. cerebral malaria 2. hyperpyrexia 3. hemolytic anemia 4. noncardiogenic pulmonary edema 5. acute tubular necrosis & renal failure 6. acute hepatopathy 7. hypoglycaemia 8. cardiac dysrhytmias 9. gastrointestinal syndromes 10. lactic acidosis 11. water and electrolyt imbalance 35
36
MALARIA Drug classification ( by chemical based ): 4-aminoquinolines : chloroquine; hydroxychloroquine; amodiaquine 8-aminoquinolines : primaquine diaminopyrimidines diaminopyrimidines : pyrimethamine pyrimethamine; trimethoprim biguanides c hlorproguanilil (folate antagonist) : proguanil; chlorguanide; chlorproguan quinoline methanol : quinine; quinidine, mefloquine sulfonamides : sulfadoxine; sulfadiazine; sulfamethoxazole folate antagonist combination : sulfadoxin – sulfadoxin – pyrimethamine (Fansidar™ ), chloroguanil - dapsone tetracycline tetracycline : doxycycline, doxycycline, clindamycin clindamycin phenanthrene methanol : halofantrine; atovaquone sesquiterpene lactone endoperoxiodes : artemisinins (qinghaosu), artesunate, artemether quinone-folate antagonist atovquone-proguanil (Malarone™) combination : atovquone-proguanil amyl alcohol : lumefantrine
MALARIA Classification based on the drug actions. Tissues schizonticides : inhibit the the growth growth of pre-erythrocyt stage of parasite (liver) proguanil; primaquine; pyrimethamine (with or without sulfonamides) causal prophylactics Antirelaps drugs : kill the dormant hypnozoites primaquine; 8-aminoquinolones indicated P.vivax & P ovale Blood schizonticides : kill the erythrocytic form, chloroquine; quinine; mefloquine can be used as suppressive prophylactics Gametocytocides : destroy the asexual stage of the parasite in the blood primaquine Sporozonticides : inhibit formation of oocyst and sporozoites in mosquitoes pyrimethamine; proguanil
Next: 3 examples of anti-malaria drugs profiles.
CHLOROQUINE MECHANISM OF ACTION : forms a toxic complex with ferriprotoporphyrine IX (haeme), class of blood schizontocide schizontocide and gametocide. Plasmodium sensitive : P. P. vivax, falciparum, ovale, ovale, malariae. Onset of drug effects : 3 hours. PHARMACOKINETIC PROFILE : F (%) : 90 t½ß (h) : 1220 (41-50 ds) Vd (L) : 57.400 CL (L/h) : 65 Prot.bind. (%) : 55 Route of elim. : kidney (unchanged) Metabolite activity : less active
ROUTE OF ADMINSTR.: Oral; Parenteral DOSAGE : 600 mg initially, 6-8 h later : 300 mg and next 2 days 300 mg (total : 1.500 mg) Duration of treatment : 3 days
ADVERSE EFFECTS: pruritis, GI upset, headache, fatigue, visual disturbances, dyskinesia, neurovascular disease LIMITATIONS : RESISTANCE. 39
MEFLOQUINE MECHANISM OF ACTION : same as chloroquine, sensitive to : Plasmodium falciparum and P. P. vivax. Class : blood schizontocide; onset : 6 hours. PHARMACOKINETICS PROFILE : F (%) : 85 t½ß (h) : 530 Vd (L) : 1330 CL (L/h) : 2.0 Prot. Bind. (%): 98 Route of elim. : faecal & renal unchanged and carboxylic acid metabolite (inactive).
ROUTE OF ADMINSTR.: Oral. DOSAGE : Initial : 750 mg. 6-8 (h) later : 500 mg and 250 mg after a further 6-8 6-8 hr hr.. DURATION OF TREATMENT: 1 (one) day day..
ADVERSE EFFECTS: dizziness, GI upset, headache, pruritis, skin rashes, CNS toxicity. toxicity. LIMITATIONS. expensive, resistance (now some area was established). 40
PRIMAQUINE MECHANISM OF ACTION : ACTION : interferes with plasmodial mitochondria function, binds to DNA. Effectve Effectve : exoerythrocytic exoerythrocytic forms of P.vivax P.vivax and P.ovale. Gametocides all forms of plasmodia. Class : tissue schizonticides / gametocide. Onset : 1 – 1 – 2 2 hours. PHARMACOKINETIC PROFILE: F (%) : 90 90 – – 100 t½ß : 4 – – 5 5 Vd (L) : 322 CL (L/h) : 56 Prot. Binding (%) : -Route of elim. : renal and faecal Metabolite less active.
ROUTE OF ADMINISTR. Oral. DOSAGES: 15 mg daily for duration of 14 days.
methaemoglobinaemia, depression, ADVERSE EFFECTS : mild anaemia, methaemoglobinaemia, confusion, cardiac arrhythmia, granulocytopenia, agranulocytosis.
41
OTHERS ANTIMALARIA. 1. Am Amod odia iaqu quin ine e 2. Qu Quin iniine 3. Su Sulf lfad adox oxin ine e – pyrimethamine (Fansidar®) 4. At Atov ovaq aquo uone ne – proquanil (Malarone®) 5. Ha Halo lofa fant ntri rine ne 6. The Art Artemi emisin sinin in drugs drugs : artesunate artemether artemisinin 7. Artemether – lumefantrine (Co-artem) 42
CHEMOPROPHYLAXIS FOR THIS PURPOSE DRUGS ACT IN TWO WAYS : AS SCHIZONTICIDES, when parasites enter the red cell they are destroyed; AS CAUSAL PROPHYLACTICS, which prevent the development of the PE schizont in the liver, and may have schizonticidal effects. Currently, chemoprophylaxis is routinely advise only for : NON-IMMUNE travellers visiting endemic area
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CHEMOPROPHYLAXIS / CHEMOPROPHYLAXIS SUPPRESSIVE DOSAGES FOR ADUL ADU LTS.
PRIMAQUINE 45 mg(base)/week for 8 weeks
CHLOROQUINE 300 mg (base) / week. PYRIMETHAMINE 25 mg/week in combination with sulfadoxine
MEFLOQUINE 250 mg/week for 4 weeks, then 125 mg/week SULFADOXINE 500 mg/week in combination with pyrimetamine 44
AMEBIASIS CAUSE : - entamoeba histolytica CLINICAL : - asymptomatic intestinal infection - mild – mild – moderate moderate intestinal infection - severe intestinal infection - hepatic abcess ameboma & other extraintestinal
MEDICINES : - Metronidazole - Tinidazole - Iodoquinol - Diloxanide furoate - Paromycin sulfate - Emetin & dehydroemetine 45
ASYMPTOMATIC ASYMPTOMATIC INTESTINAL : - diloxanide furoate 3 dd 500mg (10 days ) - iodoquinolone iodoquinolone 3 dd 650 mg (7 days) - paromomycin paromomycin 3 dd 10 mg/kg BB (7 days)
MILD – MODERA MODE RATE TE & - metronidazole metronidazol e 3 dd 750 mg or SEVERE INFECTION : 500 mg i.v./6hours (10 days ) - tinidazole tinidazole 2 g daily (3 days) + diloxanide alternative : - diloxanide + tetracycline 3 dd 250 mg (10 days) - erythromycin 4 dd 500 mg (10 days) for severe infection : dehydroemetine dehydroemetine / emetine 1 mg/kg SC or I.M (3-5 days)
HEPA HEPATIC ABCESS-AMEBOMA-ot ABCESS-AMEBOMA-other her EXTRA INTESTINAL infection infectio n : same to SEVERE INFECTION but treatment more longer (21 days)
46
2. FILARIASIS CAUSES : - Wuchereria bancrofti Culex - Brugia malayi transmitted Aedes - Brugia timori Anopheles incubation periode : 8 – 16 mo.
Cause : high degree of disability - hydrocele - scrotal lymphedema lymphedema - lymphatic varices - elephantiasis : extrimities, genitals, breasts R
- diethylcarbamasine - ivermectin only as a microfilaricide combine with diethyl carbamasine - albendazole only as a microfilaricide 47
Diethylcarbamazine citrate (DEC)
Effective : microfilaricidal, with dose 1-2 mg/kg BW 3 x daily for 2-3 weeks. Adult worms require require longer course of therapy and/or and/or multiple therapy. Adverse effects : allergic reactions, headache, vertigo, dizziness, malaise, fever, or myalgia.
PREVENTION : - reduce / eradicate population of mosquito - protect from mosquito bites
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3. ONCHOCERCIASIS CAUSE : O. VOLVULUS endemic area : Africa & Latin America A merica cause
of BLINDNESS, Dermatitis, Lymphadenitis Lymphadenitis
Transmitter: female black flies ( simulium species )
- diethylcarbamazine no effect in adult worm - ivermectin suitable for mass treatment dose : 400µg/kg single dose, often combined with a single dose albendazole 400 mg. repeated at 3-month for 2-3 years. - albendazole 400 mg 2x daily for 3 weeks ( have macrofilaricidal effects )
49
4. SCHISTOSOMIASIS CAUSED : Trematodes (blood flukes) S. mansoni (Africa; Arabian peninsula; South America; the Carabbean. S.haematobium ( Middle East and Africa ) S.mekongi (Southeast Asia) Africa) S.intercalatum (West and Central Africa) S. japonicum (Japan; China; Philippines) 3 stages : cercariae – mature flukes – eggs
R
praziq uantel praziquantel ONLY ONL Y IF LIVE OV OVA A ARE IDENTIFIE IDENTIFIED. D. oxamniquine effective only S. mansoni metrifonate -> S. hematobium
PERMASALAHAN : ketersediaan Obat cukup sulit,tersedia pada daerah ttt (Program: Indonesia – hanya di Sulawesi Tengah) 50
CLINICAL (3 CLINICAL (3 major disease syndromes): mature flukes : - dermatitis (swimmers’itch) swimmers’itch ) - fever & constituional complaints (Katayama fever) - chronic fibro-obstructive fibro-obstructive disaese DERMATITIS DERMATITIS : 1-3 days after penetration of cercariae -priritis -papular rash (rarely occur in primary exposure) KATA KATAYAMA FEVER FEV ER : 4 – 8 – 8 weeks after penetration of the human skin - severe in S japonicum; some times in S mansoni; - rare in S haematobicum CHRONIC FIBRO-OBSTRUCTIVE: FIBRO-OBSTRUCTIVE: - damage by deposition of eggs -> chronic granulomatoous disease and fibrosis. 51
LABORATORY : - eosinophilia, eosinophilia, hematurie, anemia - chronic end-stage : abnormal liver function elevated serum creatinine uremia - characteristic by : schistomia schistomia eggs (feces/urine or rectal biopsi) DIFF.DIAG : hepatic Sch -> hepatoslenomegaly & portal hypertension DD: alkoholic cirrh; Wilson’s disease; hepatitis C. S haematobium -> DD ca bladder / ureteral; CRF sometimes -> hematuria
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5. LEISHMANIASIS Syndromes :
leishmaniasis (kala azar): L.donavani; L. infantum; - Visceral leishmaniasis L. chagasi - Cutaneus leishmaniasis : leishmaniasis : Old world : world : L. tropica; L. major; L. aethiopica. New world : world : L. mexicana. - Mucocutaneus leishmaniasis (espundia) : (espundia) : Leishmania (viannia) braziliensis; rare L(v) panamensis. - Diffuse cutaneus leihmaniasis : L. mexicana; L. aethiopica
53
VISCERAL LEISHMANIASIS (KALA-AZAR) ENDEMIC : -in the South-west Asia; Asia; the Indian subcontinent; China; the Mediterranean area; east Africa; and Central and South America Clinic : -Chronic irregular fever, fever, malaise, anorexia, cough, diarrhea and secondary infections later : progressive enlargement of the spleen and liver; lymph-nodes with anemia and emaciation -Untreated fatal -After cure (in Indian subcontinent) chronic granulomatous infiltration of the skin and patchy hypopigmentation without ulceration
54
CUTANEOUS LEISHMANIASIS. The
Old World : in the Mediterranean area; western Asia; the Indian subcontinent (west area) and east and west Africa. Africa.
The
except Chile New World : in Central and South America ( except and Uruguay )
Characterized : a cell-mediated reaction at the site of inoculation; immunity develops and healing occurs by fibrosis and leaving a prominent scar.
The New World more severe and slower to heal than The Old World
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MUCOCUTANEOUS LEISHMANIASIS. ENDEMIC : South and Central America; Ethiopia and Kenya caused by L.aethiopica. Primary lesions : regional lymphangitis and lymphadenitis. Characterized : progressive ulceration and erosion of the soft tissues of the mucosa of the nose, mouth and pharynx e s p u n d i a This condition : appear soon after initial infection or many year after apparent resolution of the primary lesions.
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DIFFUSE CUTANEOUS LEISHMANIASIS ENDEMIC : Brazil; the Dominic Republic; Mexico; and Venezuela; and Ethiopia and Kenya ( L.aethiopica ) L.aethiopica ) Primary lesion : progressive, widespread, thickening and leprosy-like lesion. ( once established do not regress with treatment )
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PHARMACOTHERAPEUTIC (1)
MEGLUMINE ANTIMONATE : ANTIMONATE : inject. 85 mg/ml SODIUM STIBOGLUCONATE : STIBOGLUCONATE : inject. 100 mg/ml both contain antimony ( (Sb pentavalent ) in 5 ml ampoule.
Dosage & adminstration : adminstration : 20 mg Sb pentavalent / kg BW i.m. duration of treatment : - Visceral L., minimum L., minimum 20 days - Cutaneous L., L., local (intralesion) 1 – 3 ml interval 1-2 days systemic : 10 -20 mg until clinical cure at least 4 weeks - Mucocutaneous L., 20 L., 20 mg / kg BW i.m. until split skin smears negative, at least 4 weeks. In relapse should be retreated at least twice as long. - Diffuse cutaneous L., 20 L., 20 mg / kg BW i.m. several month until clinical improvement occurs. 58
PHARMACOTHERAPEUTIC PHARMACOTHERAPEUTIC (2) CONTRAINDICATIONS CONTRAINDICATIONS : - severe renal disorders - severe heart disorders - severe liver disorders PREGNANCY : no evidence. ADVERSE EVENTS : dose-dependent and and reversible in T-wave inversion & prolongation ECG changes, T-wave Q-T interval precede serious dysrhythmia. Hepatic and renal dysfunction impairment. Headache, malaise, dyspnoea, skin rashes, Abdominal pain and facial oedema.
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PHARMACOTHERAPEUTIC PHARMACOTHERAPEUTIC (3) Others : Pentamidine : all type of Leishmaniasis dosage : 3 – 3 – 4 4 mg / kg BW by deep i.m.or slow iv (>60’) for duration : 5 to 25 weeks. CI : renal impairment hypersensitive AE: - mild nephrotoxicity nephrotoxicity - acute hypotension and syncope ( rapid iv ) - hypoglycaemia ( pancreatic damage ), - hypocalcemia; GI effects; confusion, hallucinations; cardiac dysrhythmias; local induration ( sterile abscess); - rare : thrombocytopenia; leucopenia; Stevens-Johnson syndrome; abnormal hepatic functions. Amphotericin
B also as anti fungal. 60
TRYPANOSOMIASIS. AFRICAN
( sleeping sickness ) AMERICAN ERICAN ( Chagas diseases ) AM
AFRICAN TRYPANOSOMIASIS. Pharmacotherapeutics : 1. PENTAMIDINE. Injection 200, 300 mg each vial. 2. SURAMINE. Injection 1 g / vial. 3. MELARSOPROL. Injection 36 mg / vial. 4. EFLORNITHINE. Injection 200 mg in 100 ml ampoule. ampoule . AMERICAN TRYPANOSOMIASIS. Pharmacotherapeutics : 1. BENZNIDAZOLE. Tablet 100 mg 2. NIFURTIMOX. Tablet 30, 120 and 250 mg.
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ANTIHELMINTHIC CAUSES : WORMS : 1. ROUNDWORMS ROUNDW ORMS (NEMATODA) (NEMATODA) - ascaris lumbricoides - trichuris trichiura - necator americanus - strongyloides stercoralis - enterobius vermicularis - trichinela spiralis - cutaneus larva migran (creeping eruption) - visceral larva migran etc. 2. TREMATODES (flukes) : - schisostoma sp (haematobium; mansoni; japonicum) - fasciola hepatica; etc. 3. CESTODA (tape worms) worms ) : - taenia saginata - taenia solium - diphyllobothrium latum - echinococcus granulosus,etc 62
PHARMACOTHERAPY – ANTIHELMINTHIC (1) : ALBENDAZOLE (Ascariasis; Trichuriasis; Hookworm and Pinworms) BITHIONOL ( Fascioliasis/sheep liver flukes; alternative : pulmonary paragonimiasTIN paragonimiasTIN is ) Tropical eosinophilia) DIETHYLCARBAMACEPINE CITRATE (Filariasis; Loiasis; Tropical
DOXYCYCLINE (Filariasis; Onchocerciasis) IVERMECTIN (Strongyloidiasis; Onchocerciasis) Hookworm and Pinworm) MEBENDAZOLE (Ascariasis; Trichuriasis; Hookworm
METRIFONATE (TRICHLORFON) (Schisostoma hematobium) NICLOSAMIDE (Tapeworm) OXAMNIQUINE (Schisostoma mansoni; hematobium; japonicum) 63
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PHARMACOTHERAPY - ANTIHELMINTHIC (2): PIPERAZINE (Ascariasis) PRAZIQUANTEL ( all type Schisostoma infection; Trematoda ; Cestoda; Cysticercosis) Trichostrongylus orientalis) PYRANTEL PAMOATE (Pinworm; Ascariasis; Trichostrongylus
THIABENDAZOL ( THIABENDAZOL ( alternative to IVERMECTIN or ALBENDAZOLE; Cutaneus larva migrans/creeping eruption
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BENZIMIDAZOLE : albendazole; mebendazole; thiabendazole MECHANISM OF ACTION ACTION : - inhibiting microtubule synthesis - larvacid (cysticercosis; ascariasis; ankylostomiasis; trichuriasis) - ovicidal ADVERSE REACTION : - mild – mild – moderate moderate gastrointestnal problems (epigastric pain;diarrhea; nausea) - headache; dizziness; lassitude; insomnia (especially in long-term use) - hypersensitive - WARNING : pregnant and child < 2 year. year.
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PHARMACOKINETICS; MECHANISM MECHANIS M OF ACTION; DOSAGE; CLINICAL USES; ADVERSE REACTION; CONTRAINDICATION In detail, please refered to:
Reference: KATZUNG,BG., KA TZUNG,BG., (ed.) (e d.) 2009, , 11TH Ed., pg : 835-844; 899-922; 923-934 Lange-McGrawHill., Boston. BASIC AND CLINICAL CLI NICAL PHARMACOLOGY PHARMACOLOGY
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REFERENCES. :ANTI BIOTICS CS 1. Spice Spicerr, WJ., WJ., et al., al., 2003 2003,, Therapeutic s Guid elines :ANTIBIOTI version 12., Therapeutics Guidelines Ltd., Melbourne, Australia. Australia. 2. Todd, odd, WE. WE.,, et al., al., 199 1998, 8, C l i n i c a l P r a c t i c e G u i d e l i n e s, ADIS International Ltd., Auckland. Auckland. el e c t i o n a n d U s e o f E s s e n t i a l M ed ed i c i n e s, 3. WHO., 20 2003, T h e S el TRS – 920, Geneva. Fo r m u l a r y 4. Stua Stuart rt,M ,M C., C., et al. al.,, 2009 2009,, W H O M o d e l Fo , WHO, Geneva. 5. MIMS., No No.2 – 2006. 6. Suryawati,S Suryawati,S.. et al., al., 1990, 1990, Edisi Edisi I, Pemi Pemilihan lihan dan dan Pemakai Pemakaian an Antibiotika Antibiotika dalam klinik; Lab. Farmakologi Klinik FK-UGM – Yayasan Yayasan Melati Nusantara, Yogyakarta. 7. Katz Katzun ung, g, B G., G., 2009 2009,, 11 11th Ed, Basic and Clinical Pharmacology, McGraw Hill-Lange Publication. Boston. 8. Wlson, Wlson, WR & Sand Sande,M e,MA, A, 2001, 2001, 1st Ed., Current and Treatment Infectious Diseases, Lange Medical Books / McGraw-Hill, New York.
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