ANTIVIRAL ANTI FUNGAL ANTIPROTOZOAL ANTIHELMINTHICS

SULANTO SALEH-DANU R., dr., SpFK Clinical Pharmacology Division, Pharmacology & Therapy Departement, FACULTY of MEDICINE, UNIVERSITAS GADJAH MADA
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VIRUS BAKTERI JAMUR PARASIT dll

INFEKSI

SISTEM BIOLOGI TUBUH MANUSIA

SIMPTOM & SIGN PATOLOGIS

TUMBUH dan BERBIAK

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OBAT- OBAT ANTIINFEKSI

Obat-obat Antiviral

Obat-obat Antifungal Obat-obat Antiprotozoal

Obat-obat Antibakterial

Obat-obat Anthelmintik
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KLASSIFIKASI ANTIINFEKSI
1. BERDASARKAN JENIS MIKROORGANISME : ANTIVIRAL ANTIBAKTERIAL ANTIFUNGAL ANTIPROTOZOA ANTIPARASIT ANTHELMINTHIK 2. BERDASARKAN SIFAT TERHADAP BAKTERI : - BAKTERIOSID - BAKTERIOSTATIK 3. BERASARKAN PADA SPEKTRUM ANTI MIKRORGANISME : - BROAD SPECTRUM ( berspektrum luas ) - NARROW SPECTRUM ( berspektrum sempit ) 4. BERDASARKAN STRUKTUR / GUGUS KIMIAWI.
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EFFICACY SAFETY COSTLY

SELECTION OF MEDICINES PHARMACOTHERAPEUTICS ROUTE OF ADMINISTRATION DOSAGE FORM FREQUENY NON PHARMACO- THERAPIES DURATION ADVERSE DRUG REACTION INTERACTION

TREATMENT

DRUG DOSAGE, ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION

TROPIC- COUNTRIES SITUATION

BODYWEIGHT NUTRIONAL STATUS & DIETARY HABITS TROPICAL ENVIRONMENT: climatic factors infections and infestations environment pollutants (chemicals, mycotoxins, alcoholism, smoking, etc)

PHARMACOKINETIC

PHARMACOTHERAPY

PHARMACODYNAMIC

EFFECTS, RESPONSES, INTERACTIONS, ADVERSE EFFECTS, Etc., etc.

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AREA-CLIMATE

ABNORMLITY BY

CAUSATIVE AGENTS

ARTIC/ANTARTIC

GENETIC
4-SEASON COUNTRIES

PARASITES

diseases

DEGENERATIVE

FUNGAL

SUBTROPIC

METABOLISM

BACTERIAL

TROPIC

MALIGNANCY

VIRAL OTHERS

INFECTION
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OBAT-OBAT ANTIVIRAL
VIRUS

parasite/mikroorganisme yang hidup intraseluler host

berkembang dengan replikasi didalam sel (host) hidup metabolisme virus sangat mirip dengan metabolisme sel host sehingga sulit untuk mendapatkan obat antiviral yg selektif dan aman.

ACRONYMS & OTHER NAMES (pada virologi) 3TC AZT d4T ddC ddL FTC 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 Kaposis sarcoma-associated herpesvirus 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
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CMV

CYP

EBV HAART HBV HBC HHV-6 HIV HPV HSV KSHV NNRTI NRTI RSV VZV PI SVR

IFN

VIRAL REPLICATION & SITE OF ANTIVIRAL DRUG ACTION

Blocked by envuvirtide (HIV) maraviroc (HIV) docosanol (HSV) palivizumab (RSV)

Blocked by interferon-alfa (HBV, HCV)

1.Viral attachment & entry 2.penetration

3.uncoating
4.early protein synthesis

Blocked by amantadine, rimantadine (Influenza-A)

SEL MAMMALIA

5.nucleic acid synthesis 6.late protein synthesis & processing 7.packing & assembly

Blocked by NRTIs(HIV), NNRTIs (HIV), acyclovir (HSV), foscamet (CMV), entecavir (HBV)

8. Viral release Blocked by neuroaminidase inhibitors (influenza) Blocked by protease inhibitors (HIV)
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( Safrin,S.,2009 )

OBAT-OBAT ANTIRETROVIRAL
NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR ( NRTI ):

-Abacavir -Didanosine -Emtricitabine -Lamivudine -Stavudine -Tenofovir -Zalcitabine -Zidovudine

N0NNUCLEOSIDE ( NNRTI ) :

-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; iv & topical) *) FAMCICLOVIR (po) *) FOSCARNET (iv) *) DOCOSANOL (topical) PENCICLOVIR (topical) TRIFLURIDINE (topical) VALACYCLOVIR (po) *) *) = hati-hati pada penderita gangguan fungsi ginjal

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Acyclovir Penciclovir Ganciclovir

Virus-specified enzymes

monophosphate
(eg, thymidine kinase, UL97)

Host kinases

Trifluridine Cidofovir fasconet

diphosphate

triphosphate

Incorporation into viral DNA

Chain termination

MECHANISM of action of antiherpes agent

(Safrin, S., 2009)

Competitive inhibition of viral DNA polymerase Inhibition of viral DNA synthesis

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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 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 DOSIS HARUS HITUNG DENGAN TELITI PADA PASIEN DENGAN INSUFFISIENSI RENAL

HEPATITIS C:

Pegylated interferon alfa-2a Pegylated interferon alfa-2b Ribavirin *) Interferon alfa-2a Interferon alfa-2b Interferon alfa-2con

*) = TIDAK DIREKOMENDASI
UTK MONOTERAPI

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OBAT ANTI-INFLUENZA
-Amantadine & Rimantadine -Zanamivir & Oseltami

OBAT ANTIVIRAL lainnya

Interferon-interferon Ribavirin Palivizumab imiquimod

Catatan : detail farmakokinetik-farmakodinamik; dosis; dan ADR lihat : Sharon Safrin in BASIC & CLINICAL PHARMACOLOGY Berttram G. Katzung ; 11th Ed. 2009, pg 845 875.
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CATATAN UNTUK ANTIVIRAL

1. OBAT-OBAT YANG TERCANTUM DIATAS BEBERAPA BELUM BEREDAR DIPASARAN INDONESIA dan MASIH DALAM EARLY MARKET DAN INVESTIGASI 2. VIRUS HIDUP HANYA DIDALAM SEL HOST 3. BAHWA BERBIAKNYA VIRUS (REPLIKASI) SANGAT TERGANTUNG PADA PROSES SINTETIK SEL HOST 4. OBAT-OBAT ANTIVIRAL BISA DIKATAKAN EFEKTIF BILA MEMBLOCK MASUK-KELUARNYA VIRUS PADA SEL HOST atau AKTIF DIDALAM SEL HOST (TANPA MENGGANGGU KEHIDUPAN SEL HOST) 5. PENGOBATAN MEMBUTUHKAN WAKTU LAMA PERLU SELALU WASPADA TERHADAP ADVERSE DRUG REACTION
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ANTIFUNGAL

SYSTEMIC (infection) DRUGS (oral / parentral)

MUCOCUTANEUS INFECTION (ORAL)

MUCOCUTANEUS INFECTION (TOPICAL)

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PROBLEMATIK INFEKSI FUNGAL / JAMUR :

- JUMLAK KASUS MENINGKAT - MUNCULNYA JAMUR RESISTEN terhadap ANTIFUNGAL - DIJUMPAI : organ transplantation 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

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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
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PENGGUNAAN DI KLINIS :
- Digunakan pada penyelamatan jiwa karena infeksi jamur. - INITIAL INDUCTION dilanjutkan dengan AZOLE (severe fungal pneumonia; severe cryptococcal meningitis; dan pada penyebaran endemik mycoses ) - Pemberian : IV /infus (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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ADVERSE DRUG REACTION / ADR

-IMMEDIATE REACTION (infusion-related toxicity) 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 . -CUMULATIVE TOXICITY : Kerusakan ginjal.

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AZOLES
R
SENYAWA SINTETIK : imidazole triazole

X =C X =N

N
N

X Pharmacologic propertes of AZOLE drugs

Water sol. Absorp. variable variable high high high CSF : srm conc.rat < 0.1 < 0.01 > 0.7 --t (hours) 7 10 24 42 22 31 6 25 Elimination hepatic hepatic renal hepatic hepatic Formulation oral oral; i.v. oral; i.v. oral; i.v. oral
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Ketoconaz Itraconaz Fluconaz Voriconaz Posaconaz

low low high high low

MECHANISM OF ACTION
-REDUCTION OF ERGOSTEROL SYNTHESIS by INHIBITION OF FUNGAL CYTOCHROME P-450 ENZYMES SIFAT SELEKTIF : pada fungal affinitas CYTOCHROME-450 > manusia IMIDAZOLE selektifitas < TRIAZOLE

INTERAKSI OBAT Pada METABOLISME

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INTERAKSI OBAT Pada METABOLISME

ITRACONAZOLE + RIFAMPICINS (RIFAMPIN,RIFABUTIN,RIFAPENTINE) BIOAVAILABILITY ITRACONASOLE 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.
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ANTIPROTOZOAL / anti parasitic

MALARIA : plasmodium falciparum plasmodium vivax plasmodium malariae plasmodium ovale plasmodium knowlesi (kera) AMEBIASIS (entamoeba histolytica) intestinal amebic colitis extraintestinal amebic

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IMMUNIZATION

PREVENTIVE

MICROORGANISM / PARASIT, dll

INVASIVE

HOST

KILLED & DESTROYED

SAFE

PHARMACOTHERAPY PHARMACOTHERAPY should be :

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1. UNIQUE ENZYMES
ENZYMES PARASITES INHIBITORS

-Enzymes for dihydropteroate syntesis -Glycolipid synthesis -Pyruvate:ferrodoxin oxidoreductase -Pyruvate phosphate kinase -Nucleoside phosphotranferase

Apicomplexa African trypanosmes Anaerobic protozoa Anaerobic protozoa Flagellated protozoa

Sulfones and Sulfonamides None Nitroimidazole None Allopurinol riboside and formycine B

-Trypanothione reductase and peroxidase

Kinetoplastida

Nifurtimox

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2. INDISPENSABLE ENZYMES
ENZYMES
Lanosterol C-14 demethylase Purine phosphoribocyl transferase Purine nucleoside kinase

PARASITES
Leishmania & Trypanosoma cruzii Protozoa Trichomonas vaginalis and Entamoeba hystolytica

INHIBITORS
Azoles Allopurinol None

Ornitine decarboxylase
(S)-Adenosylmethionine decarboxylase Glycolytic enzymes

African Trypanosomes
African trypanosomes Kineplastida

-Difluoroethylornithine
Diamidines Glycerol plus salicylhydroxamic acid and suramine

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3. INDISPENSABLE BIOCHEMICAL FUNCTION WITH DIFFERENT PHARMACOLOGIC PROPERTIES

ENZYMES
Dihydrofolate reductase-thymidylate synthase bifunctional enzyme Thiamine transporter Mitochondrial electron transporter

PARASITES
Apicomplexa and Kinetoplastida Coccidia Apicomplexa

INHIBITORS
Pyrimethamine Amprolium 4-Hydroxyquinolines and 2-hydroxynaphthoquinones Benzimidazoles Levamisole, piperazine, the milbemycins, and the avermectine

Microtubules Nervous synaptic transmission

Helminth Helminth and ectoparasite

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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
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MALARIA Drug classification ( by chemical based ): 4-aminoquinolines : chloroquine; hydroxychloroquine; amodiaquine 8-aminoquinolines : primaquine diaminopyrimidines : pyrimethamine; trimethoprim biguanides (folate antagonist) : proguanil; chlorguanide; chlorproguanil quinoline methanol : quinine; quinidine, mefloquine sulfonamides : sulfadoxine; sulfadiazine; sulfamethoxazole folate antagonist combination : sulfadoxin pyrimethamine (Fansidar ), chloroguanil - dapsone tetracycline : doxycycline, clindamycin phenanthrene methanol : halofantrine; atovaquone sesquiterpene lactone endoperoxiodes : artemisinins (qinghaosu), artesunate, artemether quinone-folate antagonist combination : atovquone-proguanil (Malarone) amyl alcohol : lumefantrine
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MALARIA Classification based on the drug actions. Tissues schizonticides : inhibit the 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.

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CHLOROQUINE
MECHANISM OF ACTION : forms a toxic complex with ferriprotoporphyrine IX (haeme), class of blood schizontocide and gametocide. Plasmodium sensitive : P. vivax, falciparum, ovale, malariae. Onset of drug effects : 3 hours. PHARMACOKINETIC PROFILE : F (%) : 90 t (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.
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MEFLOQUINE
MECHANISM OF ACTION : same as chloroquine, sensitive to : Plasmodium falciparum and P. vivax. Class : blood schizontocide; onset : 6 hours. PHARMACOKINETICS PROFILE : F (%) : 85 t (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. DURATION OF TREATMENT: 1 (one) day.

ADVERSE EFFECTS: dizziness, GI upset, headache, pruritis, skin rashes, CNS toxicity. LIMITATIONS. expensive, resistance (now some area was established).
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PRIMAQUINE
MECHANISM OF ACTION : interferes with plasmodial mitochondria function, binds to DNA. Effectve : exoerythrocytic forms of P.vivax and P.ovale. Gametocides all forms of plasmodia. Class : tissue schizonticides / gametocide. Onset : 1 2 hours. PHARMACOKINETIC PROFILE: F (%) : 90 100 t : 45 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.

ADVERSE EFFECTS : mild anaemia, methaemoglobinaemia, depression, confusion, cardiac arrhythmia, granulocytopenia, agranulocytosis.

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OTHERS ANTIMALARIA.
1. Amodiaquine 2. Quinine 3. Sulfadoxine pyrimethamine (Fansidar) 4. Atovaquone proquanil (Malarone) 5. Halofantrine
6. The Artemisinin drugs : artesunate artemether artemisinin 7. Artemether lumefantrine (Co-artem)
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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 / SUPPRESSIVE DOSAGES FOR ADULTS.

CHLOROQUINE 300 mg (base) / week. PYRIMETHAMINE 25 mg/week in combination with sulfadoxine

SULFADOXINE 500 mg/week in combination with pyrimetamine

PRIMAQUINE 45 mg(base)/week for 8 weeks

MEFLOQUINE 250 mg/week for 4 weeks, then 125 mg/week

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AMEBIASIS
CAUSE : - entamoeba histolytica CLINICAL : - asymptomatic intestinal infection - mild moderate intestinal infection - severe intestinal infection - hepatic abcess ameboma & other extraintestinal

MEDICINES : - Metronidazole
- Tinidazole - Iodoquinol - Diloxanide furoate - Paromycin sulfate - Emetin & dehydroemetine
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ASYMPTOMATIC INTESTINAL : - diloxanide furoate 3 dd 500mg (10 days ) - iodoquinolone 3 dd 650 mg (7 days) - paromomycin 3 dd 10 mg/kg BB (7 days)

MILD MODERATE & - metronidazole 3 dd 750 mg or SEVERE INFECTION : 500 mg i.v./6hours (10 days ) - 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 / emetine 1 mg/kg SC or I.M (3-5 days)

HEPATIC ABCESS-AMEBOMA-other EXTRA INTESTINAL infection : same to SEVERE INFECTION but treatment more longer (21 days)

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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 - lymphatic varices - elephantiasis : extrimities, genitals, breasts

- diethylcarbamasine

- ivermectin only as a microfilaricide combine with diethyl carbamasine - albendazole only as a microfilaricide
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Diethylcarbamazine citrate (DEC)

Effective : microfilaricidal, with dose 1-2 mg/kg BW 3 x daily for 2-3 weeks. Adult worms require longer course of therapy 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

cause of BLINDNESS, Dermatitis, Lymphadenitis Transmitter: female black flies ( simulium species )

- diethylcarbamazine no effect in adult worm - ivermectin suitable for mass treatment dose : 400g/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 )

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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) S.intercalatum (West and Central Africa) S. japonicum (Japan; China; Philippines) 3 stages : cercariae mature flukes eggs

praziquantel ONLY IF LIVE OVA ARE IDENTIFIED. oxamniquine effective only S. mansoni metrifonate -> S. hematobium

PERMASALAHAN : ketersediaan Obat cukup sulit,tersedia pada daerah ttt (Program: Indonesia hanya di Sulawesi Tengah)
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CLINICAL (3 major disease syndromes): mature flukes : - dermatitis (swimmersitch) - fever & constituional complaints (Katayama fever) - chronic fibro-obstructive disaese
DERMATITIS : 1-3 days after penetration of cercariae -priritis -papular rash (rarely occur in primary exposure) KATAYAMA FEVER : 4 8 weeks after penetration of the human skin - severe in S japonicum; some times in S mansoni; - rare in S haematobicum CHRONIC FIBRO-OBSTRUCTIVE: - damage by deposition of eggs -> chronic granulomatoous disease and fibrosis.
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LABORATORY : - eosinophilia, hematurie, anemia - chronic end-stage : abnormal liver function elevated serum creatinine uremia - characteristic by : schistomia eggs (feces/urine or rectal biopsi) DIFF.DIAG : hepatic Sch -> hepatoslenomegaly & portal hypertension DD: alkoholic cirrh; Wilsons disease; hepatitis C. S haematobium -> DD ca bladder / ureteral; CRF sometimes -> hematuria

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5. LEISHMANIASIS
Syndromes :

- Visceral leishmaniasis (kala azar): L.donavani; L. infantum; L. chagasi - Cutaneus leishmaniasis : Old world : L. tropica; L. major; L. aethiopica. New world : L. mexicana. - Mucocutaneus leishmaniasis (espundia) : Leishmania (viannia) braziliensis; rare L(v) panamensis. - Diffuse cutaneus leihmaniasis : L. mexicana; L. aethiopica

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VISCERAL LEISHMANIASIS (KALA-AZAR)

ENDEMIC : -in the South-west Asia; the Indian subcontinent; China; the Mediterranean area; east Africa; and Central and South America Clinic : -Chronic irregular 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

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CUTANEOUS LEISHMANIASIS.
The Old World : in the Mediterranean area; western Asia; the Indian subcontinent (west area) and east and west Africa.
The New World : in Central and South America ( except Chile 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 espundia 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 ) Primary lesion : progressive, widespread, thickening and leprosy-like lesion. ( once established do not regress with treatment )

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PHARMACOTHERAPEUTIC (1)
MEGLUMINE ANTIMONATE : inject. 85 mg/ml SODIUM STIBOGLUCONATE : inject. 100 mg/ml both contain antimony (Sb pentavalent) in 5 ml ampoule. Dosage & adminstration : 20 mg Sb pentavalent / kg BW i.m. duration of treatment : - Visceral L., minimum 20 days - Cutaneous L., local (intralesion) 1 3 ml interval 1-2 days systemic : 10 -20 mg until clinical cure at least 4 weeks - Mucocutaneous 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 mg / kg BW i.m. several month until clinical improvement occurs.
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PHARMACOTHERAPEUTIC (2)
CONTRAINDICATIONS : - severe renal disorders - severe heart disorders - severe liver disorders
PREGNANCY : no evidence. ADVERSE EVENTS : dose-dependent and reversible in ECG changes, T-wave inversion & prolongation 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 (3)
Others : Pentamidine : all type of Leishmaniasis dosage : 3 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 - 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.
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TRYPANOSOMIASIS.
AFRICAN ( sleeping sickness ) AMERICAN ( Chagas diseases )

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. 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 (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) : - taenia saginata - taenia solium - diphyllobothrium latum - echinococcus granulosus,etc
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PHARMACOTHERAPY ANTIHELMINTHIC (1) :

ALBENDAZOLE (Ascariasis; Trichuriasis; Hookworm and Pinworms) BITHIONOL ( Fascioliasis/sheep liver flukes; alternative : pulmonary paragonimiasTIN is ) DIETHYLCARBAMACEPINE CITRATE (Filariasis; Loiasis; Tropical eosinophilia) DOXYCYCLINE (Filariasis; Onchocerciasis) IVERMECTIN (Strongyloidiasis; Onchocerciasis) MEBENDAZOLE (Ascariasis; Trichuriasis; Hookworm and Pinworm) METRIFONATE (TRICHLORFON) (Schisostoma hematobium) NICLOSAMIDE (Tapeworm) OXAMNIQUINE (Schisostoma mansoni; hematobium; japonicum)
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PHARMACOTHERAPY - ANTIHELMINTHIC (2):

PIPERAZINE (Ascariasis)

PRAZIQUANTEL ( all type Schisostoma infection; Trematoda ; Cestoda; Cysticercosis)

PYRANTEL PAMOATE (Pinworm; Ascariasis; Trichostrongylus orientalis)

THIABENDAZOL ( alternative to IVERMECTIN or ALBENDAZOLE; Cutaneus larva migrans/creeping eruption

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BENZIMIDAZOLE : albendazole; mebendazole; thiabendazole MECHANISM OF ACTION : - inhibiting microtubule synthesis - larvacid (cysticercosis; ascariasis; ankylostomiasis; trichuriasis) - ovicidal ADVERSE REACTION : - mild moderate gastrointestnal problems (epigastric pain;diarrhea; nausea) - headache; dizziness; lassitude; insomnia (especially in long-term use) - hypersensitive - WARNING : pregnant and child < 2 year.

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PHARMACOKINETICS; MECHANISM OF ACTION; DOSAGE; CLINICAL USES; ADVERSE REACTION; CONTRAINDICATION In detail, please refered to:

Reference: KATZUNG,BG., (ed.) 2009, BASIC AND CLINICAL PHARMACOLOGY , 11TH Ed., pg : 835-844; 899-922; 923-934 Lange-McGrawHill., Boston.
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THANK YOU & WASSALAMUALAIKUM WR WB

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REFERENCES. 1. Spicer, WJ., et al., 2003, Therapeutics Guidelines :ANTIBIOTICS version 12., Therapeutics Guidelines Ltd., Melbourne, Australia. 2. Todd, WE., et al., 1998, Clinical Practice Guidelines, ADIS International Ltd., Auckland. 3. WHO., 2003, The Selection and Use of Essential Medicines, TRS 920, Geneva. 4. Stuart,M C., et al., 2009, WHO Model Formulary, WHO, Geneva. 5. MIMS., No.2 2006. 6. Suryawati,S. et al., 1990, Edisi I, Pemilihan dan Pemakaian Antibiotika dalam klinik; Lab. Farmakologi Klinik FK-UGM Yayasan Melati Nusantara, Yogyakarta. 7. Katzung, B G., 2009, 11th Ed, Basic and Clinical Pharmacology, McGraw Hill-Lange Publication. Boston. 8. Wlson, WR & Sande,MA, 2001, 1st Ed., Current and Treatment Infectious Diseases, Lange Medical Books / McGraw-Hill, New York.

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