Dr.saleh-26 March 2013-Farmakologi (Anti Jamur, Anti Virus, Anti Parasit, Dll)

5/28/2018 Dr.saleh-26 March 2013-Farmakologi (Anti Jamur, Anti Virus, Anti Parasit, Dll)

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ANTIVIRALANTI FUNGAL

ANTIPROTOZOALANTIHELMINTHICS

SULANTO SALEH-DANU R., dr., SpFK

Clinical Pharmacology Division,

Pharmacology & Therapy Departement,

FACULTY of MEDICINE,

UNIVERSITAS GADJAH MADA


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INFEKSI

SISTEM BIOLOGITUBUH MANUSIA

TUMBUH dan

BERBIAK

SIMPTOM & SIGN

PATOLOGIS

VIRUS

BAKTERIJAMUR

P R SITdll


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Obat

-

obat

Antibakterial

Obat

-

obat

Antifungal

Obat

-

obat

Antiprotozoal

Obat

-

obat

Anthelmintik

OBAT- OBAT ANTIINFEKSI

Obat

-

obat

Antiviral

3


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KLASSIFIKASI ANTIINFEKSI

1. BERDASARKAN JENIS MIKROORGANISME :

ANTIVIRAL

ANTIBAKTERIAL

ANTIFUNGAL

ANTIPROTOZOA

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.

ANTIPARASIT

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NON PHARMACO- THERAPIES

PHARMACOTHERAPEUTICS

SELECTION OF MEDICINES

ROUTE OF ADMINISTRATION

DOSAGE FORM

FREQUENY

DURATION

ADVERSE DRUG REACTION

INTERACTION

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EFFICACY

SAFETY

COSTLY

TREATMENT


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PHARMACOKINETIC

PHARMACODYNAMIC

BODYWEIGHT

NUTRIONAL STATUS &

DIETARY HABITS

TROPICAL ENVIRONMENT:climatic factors

infections and infestations

environment pollutants(chemicals,

mycotoxins, alcoholism,

smoking, etc)

DRUG DOSAGE,

ABSORPTION,

DISTRIBUTION,

METABOLISM,

EXCRETION

TROPIC- COUNTRIES

SITUATION

EFFECTS,

RESPONSES,

INTERACTIONS,

ADVERSE EFFECTS,

Etc., etc.

PHARMACOTHERAPY

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diseases

AREA-CLIMATE ABNORMLITY BY CAUSATIVE AGENTS

TROPIC

SUBTROPIC

4-SEASON COUNTRIES

ARTIC/ANTARTIC

GENETIC

DEGENERATIVE

METABOLISM

MALIGNANCY

INFECTION

OTHERS

PARASITES

FUNGAL

BACTERIAL

VIRAL

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OBAT-OBAT ANTIVIRAL

V RUSparasite/mikroorganisme yang hidup

intraseluler host

berkembang dengan replikasididalam sel (host) hidup

metabolisme virus sangat mirip

denganmetabolismesel hostsehingga sulit untuk mendapatkan

obat antiviral yg selektif dan aman.


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ACRONYMS & OTHER NAMES (pada virologi)

3TC LamivudineAZT Zidovudine (previously azido-thymidine)

CMV CytomegalovirusCYP Cytochrome P450 (enzym)

d4T StavudineddC ZalcitabineddL Didanosine

EBV Epstein-Barr virusFTC Emtricitabine

HAART Highly active antiretroviral therapy(aksi/potensi)

HBV Hepatitis B virusHBC Hepatitis C virusHHV-6 Human herpesvirus-6HIV Human immunodeficiency virusHPV Human papillomavirusHSV Herpes simplex virus

IFN InterferonKSHV Kaposis sarcoma-associated herpesvirus

NNRTI Nonnucleoside reverse transcriptase inhibitor(aksi)

NRTI Nucleoside reverse transcriptase inhibitor(aksi)

PI Protease inhibitor (aksi/site of action)RSV Respiratory syncytial virus

SVR Sustained antiviral response (response)

VZV Varicella-zoster virus


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1.Viral attachment& entry

2.penetration3.uncoating

4.early protein

synthesis

5.nucleic acidsynthesis

6.late protein

synthesis &

processing

7.packing &

assembly8. Viral release

Blocked by

envuvirtide (HIV)

maraviroc (HIV)

docosanol (HSV)

palivizumab (RSV)

Blocked by

amantadine,

rimantadine

(Influenza-A)

Blocked by

interferon-alfa

(HBV, HCV)

Blocked by

NRTIs(HIV),

NNRTIs (HIV),

acyclovir (HSV),

foscamet (CMV),

entecavir (HBV)

Blocked by

protease inhibitors

(HIV)

Blocked by

neuroaminidase

inhibitors

(influenza)

VIRAL REPLICATION & SITE OF

ANTIVIRAL DRUG ACTION

( Safri n,S.,2009 )

SEL MAMMALIA


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OBAT-OBAT ANTIRETROVIRAL

NUCLEOSIDE & NUCLEOTIDEREVERSE TRANSCRIPTASE

INHIBITOR ( NRTI ): -Abacavir-Didanosine

-Emtricitabine

-Lamivudine

-Stavudine-Tenofovir

-Zalcitabine

-Zidovudine

N0NNUCLEOSIDE ( NNRTI ) :-delavirdine

-etravirine

-efavirens

-nevirapine


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FUSION INHIBITORS : enfuvirtide

CCR5 receptor antagonists : maraviroc

INTEGRASE INHIBITORS : raltegravir

PROTEASE INHIBITORS ( PI ) :Amprenavir

Atazanavir

Darunavir

FosamprenavirIndinavir

Lopinavir/Ritonavir

Nelfinavir

Saquinavir

Tripanavir


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OBAT-OBAT UNTUK FARMAKOTERAPI DAN PREVENTIF

terhadap :

INFEKSI HERPES SIMPLEX VIRUS ( HSV ) danVARICELLA-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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monophosphate

diphosphate

triphosphate

Hostkinases

Competitive inhibition

of viral DNA polymerase

Inhibition of viral

DNA synthesis

Incorporation intoviral DNA

Chain

termination

Acyclovir

Penciclovir

Ganciclovir

Virus-specified enzymes

(eg, thymidine kinase,

UL97)

Trifluridine

Cidofovir

fasconet

MECHANISM

of act ion of

ant iherpes

agent

(Safrin , S., 2009)


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OBAT-OBAT UNTUK FARMAKOTERAPI

INFEKSICYTOMEGALOVIRUS ( 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

HEPATITIS C: Pegylated interferon alfa-2aPegylated interferon alfa-2b

Ribavirin *)

Interferon alfa-2a

Interferon alfa-2b

Interferon alfa-2con

*)= TIDAK DIREKOMENDASIUTK MONOTERAPI

DOSIS HARUSHITUNG DENGAN

TELITI PADA

PASIEN DENGAN

INSUFFISIENSI RENAL


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

OBAT ANTIVIRAL lainnyaInterferon-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 UNTUKANTIVIRAL

1. OBAT-OBAT YANG TERCANTUM DIATAS BEBERAPA

BELUM BEREDAR DIPASARAN INDONESIA dan MASIHDALAM EARLY MARKETDAN 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

MEMBLOCKMASUK-KELUARNYA VIRUS PADA SEL HOST

atau AKTIFDIDALAM SEL HOST (TANPA MENGGANGGU

KEHIDUPAN SEL HOST)

5. PENGOBATAN MEMBUTUHKAN WAKTU LAMAPERLU

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 LUASpada pasiem kritis (superinfeksi).

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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 : gangguanintraseluler ion dan macromolekul

berakibat kematian sel fungi.

SPEKTRUM ANTIFUNGAL : - luas

Candida albicansCryptococcus 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 (infu sio n-related tox icity )

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

SENYAWA SINTETIK : imidazole = C

triazole = N

NX

N

R X

X

Water sol. Absorp. CSF : srm

conc.rat

t (hours) Elimina-

tion

Formulat-

ion

Ketoconaz low variable < 0.1 710 hepatic oral

Itraconaz low variable < 0.01 24

42 hepatic oral; i.v.

Fluconaz high high > 0.7 2231 renal oral; i.v.

Voriconaz high high -- 6 hepatic oral; i.v.

Posaconaz low high -- 25 hepatic oral

Pharmacologic propertes of AZOLE drugs

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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

PadaMETABOLISME

ITRACONAZOLE + RIFAMPICINS

(RIFAMPIN,RIFABUTIN,RIFAPENTINE)

BIOAVAILABILITY ITRACONASOLE berkurang.

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ANTIPROTOZOAL /

anti parasitic

MALARIA : plasmodium falciparum

plasmodium vivax

plasmodium malariae

plasmodium ovale

plasmodium knowlesi (kera)

AMEBIASIS (entamoeba histolytica)

intestinal

amebic colitisextraintestinal amebic

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HOSTMICRO-

ORGANISM /

PARASIT, dll

INVASIVE

PHARMACOTHERAPY

KILLED & DESTROYED SAFE

PHARMACOTHERAPY

should be :

PREVENTIVEIMMUNIZATION

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2. INDISPENSABLE ENZYMES

ENZYMES P R SITES INHIBITORS

Lanosterol C-14demethylase Leishmania & Trypanosoma cruzii Azoles

Purine phosphoribocyl transferase Protozoa Allopurinol

Purine nucleoside kinase Trichomonas vaginalis and None

Entamoeba hystolytica

Ornitine decarboxylase African Trypanosomes -Difluoroethylornithine

(S)-Adenosylmethionine African trypanosomes Diamidines

decarboxylase

Glycolytic enzymes Kineplastida Glycerol plus salicyl-hydroxamic acid and

suramine


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3. INDISPENSABLE BIOCHEMICAL FUNCTION

WITH DIFFERENT PHARMACOLOGIC PROPERTIES

ENZYMES P R SITES INHIBITORSDihydrofolate reductase-thymidylate Apicomplexa and Kineto- Pyrimethamine

synthase bifunctional enzyme plastida

Thiamine transporter Coccidia Amprolium

Mitochondrial electron transporter Apicomplexa 4-Hydroxyquinolines

and

2-hydroxynaphthoquinones

Microtubules Helminth Benzimidazoles

Nervous synaptic transmission Helminth and Levamisole, piperazine,ectoparasite the milbemycins, and

the avermectine


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MALARIA

Drug classification ( by chemical based ):

4-aminoquinolines : chloroquine; hydroxychloroquine; amodiaquine8-aminoquinolines :primaquine

diaminopyrimidines : pyrimethamine; trimethoprim

biguanides

(folate antagonist) : proguanil; chlorguanide; chlorproguanil

quinoline methanol : quinine; quinidine, mefloquine

sulfonamides : sulfadoxine; sulfadiazine; sulfamethoxazolefolate antagonist combination :

sulfadoxinpyrimethamine (Fansidar ),

chloroguanil - dapsone

tetracycline : doxycycline, clindamycin

phenanthrene methanol : halofantrine; atovaquone

sesquiterpene lactoneendoperoxiodes :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 hypnozoitesprimaquine;

8-aminoquinolonesindicated P.vivax & P ovaleBlood schizonticides : kill the erythrocytic form,chloroquine;

quinine; mefloquinecan be used as suppressive prophylactics

Gametocytocides : destroy the asexual stage of the parasite in the

bloodprimaquine

Sporozonticides : inhibit formation of oocyst and sporozoites inmosquitoespyrimethamine; 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 : ROUTE OF ADMINSTR.:

F (%) : 90 Oral; Parenteral

t (h) : 1220 (41-50 ds) DOSAGE : 600 mg initially,

Vd (L) : 57.400 6-8 h later : 300 mgCL (L/h) : 65 and next 2 days 300 mg

Prot.bind. (%) : 55 (total : 1.500 mg)

Route of elim. : kidney (unchanged) Duration of treatment :

Metabolite activity : less active 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 : ROUTE OF ADMINSTR.:

F (%) : 85 Oral.

t (h) : 530

Vd (L) : 1330 DOSAGE: Initial : 750 mg.

CL (L/h) : 2.0 6-8 (h) later : 500 mgProt. Bind. (%): 98 and 250 mg after a

Route of elim. : faecal & renal further 6-8 6-8 hr.

unchanged and DURATION OF TREATMENT:

carboxylic acid 1 (one) day.

metabolite (inactive).

ADVERSE EFFECTS:

dizziness, GI upset, headache, pruritis, skin rashes, CNS toxicity.

LIMITATIONS.

expensive, resistance (now some area was established).40


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PRIMAQUINE

MECHANISM OF ACTION: interferes with plasmodial mitochondria function,

binds to DNA. Effectve : exoerythrocytic forms of P.vivax andP.ovale. Gametocides all forms of plasmodia.

Class : tissue schizonticides / gametocide. Onset : 12 hours.

PHARMACOKINETIC PROFILE: ROUTE OF ADMINISTR.

F (%) : 90100 Oral.

t : 45Vd (L) : 322 DOSAGES: 15 mg daily

CL (L/h) : 56 for duration of 14 days.

Prot. Binding (%) : --

Route of elim. : renal and faecal

Metabolite less active.

ADVERSE EFFECTS: mild anaemia, methaemoglobinaemia, depression,

confusion, cardiac arrhythmia, granulocytopenia, agranulocytosis.

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OTHERS ANTIMALARIA.

1. Amodiaquine

2. Quinine

3. Sulfadoxinepyrimethamine (Fansidar)

4. Atovaquoneproquanil (Malarone)5. Halofantrine

6. The Artemisinin drugs :

artesunate

artemetherartemisinin

7. Artemetherlumefantrine (Co-artem)

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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

MEFLOQUINE

250 mg/week

for 4 weeks, then

125 mg/week

PRIMAQUINE

45 mg(base)/week

for 8 weeks

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AMEBIASIS

CAUSE : - entamoeba histolytica

CLINICAL : - asymptomatic intestinal infection

- mildmoderate 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)

MILDMODERATE & - 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 Anophelesincubation periode :

8 16 mo.

Cause : high degree of disability- hydrocele- scrotal lymphedema- lymphatic varices- elephantiasis : extrimities, genitals, breasts

R - diethylcarbamasine- ivermectinonly as a microfilaricide combine with

diethyl carbamasine- albendazoleonly as a microfilaricide

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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 : cercariaemature flukeseggs

R 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: Indonesiahanya

di Sulawesi Tengah)

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CLINICAL (3 j di d )


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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 : 48 weeks after penetration of the human skin

- severe in S japonicum; some times in

S mansoni;

- rare in S haematobicumCHRONIC FIBRO-OBSTRUCTIVE:

- damage by deposition of eggs ->

chronic granulomatoous disease and fibrosis.


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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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BENZIMIDAZOLE: albendazole; mebendazole; thiabendazole

MECHANISM OF ACTION : - inhibiting microtubule synthesis- larvacid (cysticercosis; ascariasis;

ankylostomiasis; trichuriasis)

- ovicidal

ADVERSE REACTION : - mildmoderate 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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THANK YOUW SS L MU L IKUM WR WB


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Dr.saleh-26 March 2013-Farmakologi (Anti Jamur, Anti Virus, Anti Parasit, Dll)

Documents

dll 9729acronyms other

dll 572non pharmaco

faculty of medicine

farmakologi anti jamur

spektrum anti mikrorganisme