Anti-Biotik

(1)

Antibiotika

- Antibiotika -

Kemoterapi

Akhmad Ed

y Purwoko

Bagian

Farmakologi

& T

oksikologi

F

(2)

(3)



BASIC BIOLOGY OF CELLS



 Molecular/Cellular-intervention /therapiesMolecular/Cellular-intervention /therapies

(Pharmacodynamic & Pharmacokinetic)



 Single organ/Organ system-TherapeuticSingle organ/Organ system-Therapeutic

intervention



 Pharmacological interventionsPharmacological interventions



 Potential side effects of Potential side effects of pharmacologpharmacologicalical

intervention intervention



 Manifestation of drug Manifestation of drug toxicitytoxicity

KNOWLEDGE BASE

(4)



HEALTH OF FAMILIES



 Whole person/Family-intervention andWhole person/Family-intervention and

therapies



 Theories and principles Theories and principles of individual-orientedof individual-oriented

interventions interventions



 Theories and principles of Theories and principles of family-orientefamily-orientedd

intervention intervention



 Pharmacological interventionPharmacological intervention



 Preventive/DevelopmenPreventive/Developmental tal EncountersEncounters

Infancy, Childhood, Adolescence, Adult,

Elders, Pregnancy



(5)



Community



 Issues in the healt care Issues in the healt care system: availabilitysystem: availability

& accessebility

& accessebility __ utilizationutilization



 CostCost



 Quality & acceptabilityQuality & acceptability



Medical Encounters



 (Acut, Emergency, Chronic) Encounters-(Acut, Emergency, Chronic)

Encounters-(Pregnancy, Fetus/Neonate, Children,

(Pregnancy, Fetus/Neonate, Children,

Adolescence, Adu

Adolescence, Adult & Elders)lt & Elders) __ ClinicalClinical

Pharmacology

Pharmacology (Antibiotic drug usage) ~(Antibiotic drug usage) ~

infectious diseases

(6)

(7)

 Antibiotika Suatu zat yg dihasilkan oleh mikroorganisme yg punya kemampuan membunuh atau menghambat pertumbuhan mikroorganisme lain penyebab penyakit  Kemoterapi

Suatu zat sintetik yg punya kemampuan membunuh atau menghambat pertumbuhan mikroorganisme penyebab penyakit

Pengertian antibiotika telah mengalami pergeseran karena banyak jenis antibiotika yang sudah dapat Dibuat (disintesis, semisintesis / sintetik penuh)

(8)

Fleming

Chain

Florey Heatly

(9)

Penicillin was the first antibiotic that was successfully used in treating Penicillin was the first antibiotic that was successfully used in treating bacterial infections. Before its

bacterial infections. Before its development, many people suffereddevelopment, many people suffered and died from bacterial infections

and died from bacterial infections that are no longer consideredthat are no longer considered dangerous today

dangerous today. For instance, j. For instance, just hurting yourself on a ust hurting yourself on a nail couldnail could eventually lead to death.

(10)



Penisilin



Penicillium notatum



Streptomisin



Streptomyces griceus



Oksitetrasiklin



Streptomyc

es

rimosus



Klortetrasiklin



Streptomyces

aureofaciens



Kloramfenikol



Streptomyces

Venezuleae

Sekarang turunan penisilin ( Amoksisilin )

dan beberapa antibiotik lain

(11)

History



 Cina & Yunani kunaCina & Yunani kuna  antibiotik & kemoterapi sejakantibiotik & kemoterapi sejak

25 abad yl 25 abad yl   19281928  PenisilinPenisilin   19301930  SulfonamidSulfonamid   19441944  StreptomisinStreptomisin   19471947  KloramfenikolKloramfenikol   19481948  KlortetrasiklinKlortetrasiklin 

 19481948  SefalosforiSefalosforin (dipakai n (dipakai th 1960an)th 1960an)



 19491949  NeomisinNeomisin



 19501950  KanamisinKanamisin



 20 th berikut20 th berikut  Aminogli Aminoglikosid (gentamisinkosid (gentamisin,,

amikasin, tobramisin) & antibiotik sintetik (ampisilin, amikasin, tobramisin) & antibiotik sintetik (ampisilin, amoksisilin, siprofloksasin dsb.)

(12)

Penggolong

an

antibiotika



Berdasarkan kemampuan membunuh

kuman



Berdasar jenis bakteri yang dibunuh /

dihambat pertumbuhannya



Penggolongan berdasar struktur kimia



Penggolongan berdasar cara kerja

dalam membunuh atau menghambat

pertumbuhan bakteri

(13)

Penggolongan antibiotik



Berdasar kemampuan membunuh

kuman

 Bakterisid (membunuh kuman): penisilin,

sefalosporin, streptomisin, neomisin, kanamisin, gentamisin, dan basitrasin

 Bakteriostatik (menghambat

perkembangan bakteri): sulfonamid, trimetoprim, kloramfenikol, tetrasiklin, linkomisin & klindamisin.

 Antibiotik tertentu (INH & Eritromisin): dosis

rendah bakteriostatik, dosis tinggi bakterisid

(14)



Berdasar jenis bakteri yang dibunuh /

dihambat

 Efektif pada bakteri gram positif  Efektif pada bakteri gram negatif

 Efektif pada kedua jenis bakteri (broad

(15)

(16)



Penggolongan berdasar struktur kimia:

 Penisilin, sefalosporin, aminoglikosid,

tetrasiklin, makrolid, quinolon, kloramfenikol



Penggolongan berdasar cara kerja

dalam menghambat atau membunuh

bakteri:

(17)

1 2

3 4

Cell wall Synthesis Inhibitor

Protein Synthesis Inhibitor

Cytoplasmic Membrane Inhibitor

Nucleic Acid Synthesis Inhibitor F A R M A K O D I N A M I K

(18)

(19)

Basitrasin Vankomisin

Amfoterisin Nistatin

Sulfonamid, Trimetoprim Metronidazol, INH, Asam Nalidiksat, vidarabin, Acyclovir Linkomisin Klindamisin 1 2 3 4

(20)

TRANSLOKASI

(absorpsi, distribusi dan ekskresi)

tubuh

vasa darah intraselluler sel obat Transfer transmembran F A R M A K O K I N E T I K

(21)

F A R M A K O K I N E T I K

(22)

Figure : Active transport of antibiotics in eucaryotes

Schematic representation of the main transporters potentially

involved in antibiotic movement at the level of epithelial cells in the main organs (liver, bronchial tree, intestine, kidney), the

blood-brain barriers, and in leucocytes (PMN are not considered here since the role of drug transporters in these cells is unclear).

Black arrows denote transport towards extracorporeal

compartments such as urine, bile, intestine and airways (i.e. transporters involved in drug elimination from the body). Grey arrows describe uptake processes from extracorporeal fluids into cells (i.e. allowing drugs to accumulate in tissues), or from cells to body fluids (i.e. causing the drug to be transported from one body fluid to another [from blood to cerebrospinal fluid, e.g.]).

The level of expression of each transporter may differ between species (arrows with a checkerboard background indicate

transporters that have been, so far, evidenced in animals

only). The direction of transport of bidirectional transporters may differ according to the cell type.

F A R M A K O K I N E T I K

(23)

Quinolon



Merupakan

fluorinasi asam

nalidixic



Aktivitas

antibakteri

menghambat

gram - & gram

+

(24)

(25)



Farmakokinetik

 Absorpsi baik pd pemberian PO

 Distribusi luas ke cairan tubuh dan jaringan  Waktu paruh plasma 3-8 jam

 Setelah pemberian 400-600 mg, kadar

puncak ciprofloxacin 1-2 g/ml, ofloxacin 10 g/ml

 Ekskresi tu/ sekresi tubulardi ginjal, 20 %

(26)



Penggunaan klinik

 UTI pd mutidrug-resistant (pseudomonas)  norfloxacin 400 mg atau ciprofloxacin 500

mg dua kali sehari efektif untuk diare

(shigella, salmonella, E coli, Helicobacter

 Infeksi jaringan lunak, tulang, sendi, GIT

(27)



Adverse effect

 Nausea, vomitus, diare

 Sakit kepala, pusing, insomnia, gangguan

fungsi hati, skin rash

 Superinfeksi streptokokus, kandida



Interaksi

 Meningkatkan kadar plasma teofilin 

(28)

(29)

Mekanisme aksi Sulfonamid & Trimetoprim

(30)

Farmakokinetik



Sulfamethoxazol

 Bioavaibility 100 %

 Volume distribusi : 0.3 l/kg  Ikatan protein plasma: 65 %  Waktu paruh plasma 11 jam

 Eliminasi 20 % dieleminasi renal tanpa

diubah, sisanya dimetabolisme dalam hati menjadi metabolit yg tidak aktif (asetilasi & glukoronidasi)

Asetilasi  senyawa sukar larut dalam asam

(31)



Trimetoprim

 Bioavailibility 100 %

 Volume distribusi: 1,8 l/kg  Ikatan protein plasma: 44 %  Waktu paruh 10 jam

 Eliminasi: 70 % dieliminasi renal tanpa

diubah, sisanya dimetabolisme menjadi metabolit yg bersifat aktif farmakologik



Dosis dewasa

 PO TMP 320 mg/hr SM 1600 mg/hr (max.

TMP 420 SM 2400) pemberian tiap 8-12 jam, IV infus singkat setiap 8-12 jam

(32)



Kadar terapeutik dalam plasma

 Setelah emberian 160 mg TMP dan 800

mg SM dicapai kadar 1,5-4 g/ml dan SM 40-100 g/ml

(33)



Efek yang tidak diharapkan

 Sakit dan trombophlebitis ditempat

penyuntikan

 Mual, muntah, sakit perut, mencret

 Ulcerasi esofagus bila minum dg < cairan  Leukopenia, trombositopenia, pancytopeni,

(jarang) agranulositois

 Anemi megaloblastik  def asam folat  Jarang: sakit kepala, pusing, sukar tidur,

pendengaran bising, ataxia, serangan kram serebral, depresi halusinasi

 Jarang hipotrotrombinemia, kadang terjadi

(34)

 Peninggian kreatinin serum, Cylindriuria,

kristaluria (kristal sulfonamid dlm urin)

 Jarang: peninggian transaminase, hepatitis

cholestatik, nekrose hati, pankreatitis

 Penting dalam klinik: exantema, urtikaria,

rangsangan gatal, demam, fotosensibilitas, jarang: anafilaksi, dermatitis eksfoliativa,

steven johnson sindrom, vaskulitis nekrotikan, SLE

 Dlm cairan infus Na-disulfit & Na-sulfit 

reaksi hipersensitivitas & serangan asma pd pasien disposisi

(35)



Interaksi obat

 Antasida menurunkan absorpsi sulfonamid  Peningkatan efek: antikoagulan oral,

antidiabetika oral, methotrexat, fenitoin, fenilbutazon

 Pemberian + tiazid  trombositopenia tu/

pada usila

 Kombinasi dg chloroquin, pyrimetamin,

fenitoin, fenobarbital, primidion,

methotrexat  Anemi megaloblastik

(36)

Penisilin

 Bekerja dengan menghambat sintesis

(37)

(38)

(39)

Transpeptidase

Penisilin, cephalosporin, basitrasin vankomisin

(40)

(41)

Penisilin



Penisilin generasi pertama hrs diberikan

secara injeksi



Penisilin-G larut dlm lemak



Penisilin G yg diberikan sbg depo



benzatin penisilin-G



Pemberian prokain bersama penislin-G

(42)



Dpt diberikan peroral



thn thd enzim

pencernaan



Absorpsi dipengaruhi adanya makanan

(43)



Aborbsi lebih baik dibanding ampisilin

meskipun ada makanan dalam lambung



Ampisilin, amoksisilin, karbanesilin,

tikarsilin tidak tahan thd enzim

-laktamase



(+) as. Klavulanat /

sulbaktam

(44)

(45)

(46)

 Penisilin semisintetik Oksasilin, Kloksasilin,

Metisilin, dikloksasilin, dan nafsilin  tahan terhadap penisilinase

 Efek samping yang dapat timbul pada

pemberian penisilin: alergi (urtikaria yg ringan sampai sindrom Steven-Johnson)

 Efek toksik: iritasi SSP; iritasi lokal (nyeri,

indurasi, tromboflebitis); degenerasi saraf, pd PO: mual, muntah, diare; granulositopeni

(47)



Obat obat kelompok penisilin

 Benzylpenisilin (penisilin-G, Prokain

penisilin)

 Oral penisilin: penisilin V, propicilin

 Tahan penisilinase: oxaillin, dicloxacillin,

flucloxacillin

 Penisilin spektrum luas: ampicillin,

amoxicillin, epicillin, azlocillin, mezocillin, piperacillin, apalcillin, carbanecillin,

(48)

Sefalosporin



Sefalosporin merupakan antibiotika

-laktam seperti penisilin

(49)

Aktifitas gram + dan gram_– (broad spectrum), relatif non toksik Unt UTI, infeksi stafilokokus, infeksi polimikrobial (cellulitis, abses)

(50)

Bisa diberikan Oral, IV. Cefuroxim dpt melewati sawar darah otak Digunakan unt meningitis dan sepsis

(51)

Ceftriaxon, Cefoperazon  IV, ekskresi bilier; Cefixim dpt PO diekskresi melalui ginjal

Kecuali cefoperazon & cefixim penetrasi ke SSP baik

(52)



Berdasar ciri & sifat obat dibagi:

 Sefalosporin parenteral (basic cephalosporin)

cefalotin, Cefazolin & Cefacedon, tdk tahan -laktamase

 Sefalosporin psrenteral lebih tahan

-laktamase (transitional cephalosporin) cefamandol, cefuroxim, cefotiam

 Sefalosporin parenteral efektif thd bakteri

anaerob & tahan -laktam: cefotixin, cefotetan

 Sefalosporin spectrum luas & tahan

-laktamase: cefotaxim, ceftizoxim, cefmenoxom, ceftriaxon, ceftasidim, cefoperaxon, cefixim

(53)

 Sefalosporin PO tidak tahan -laktamase (older

oral cephalosporin): cefradin, cefalexin, cefadroxil, cefaclor, cefonicid, cefixim

 Sefalosporin PO (stabil) tahan -laktamase

(more recent cephalosporin): cefuroxim axetil 

Advers efffect

 Alergi: hipersensisitf, fever, rash, nefritis,

granulositopenia, anemia hemolitik

 Efek toksik: iritasi lokal  nyeri, tromboflebitis;

nefritis, ATN; hipoprotrombinemia, gangguan perdarahan;

(54)

Kloramfenikol



Cara kerja menghambat sintesis protein

ribosom



Penghambatan mitokondria pd mamalia



depresi sumsum tulang



anemia

aplastik



PO aborpsi baik & dpt menembus

sawar darah otak.

(55)



Farmakokinetik

 Bioavailibility 80 %

 Volume distribusi 0,6 l/kg (LCS 50 % kadar

plasma, pd meningitis

_–

100 %)

 Ikatan protein plasma: 60 %, pada BBL &

cirosis 40 %

 Waktu paruh plasma 3 jam, BBL & cirosis 6

jam

 Eliminasi: 10 % oleh ginjal tanpa diubah,

sebagian besar diglukoronidasi dalam hati

 Dosis 20-30(40) mg/kg/hr max 3 g dewasa  Kadar terapeutik 5-20 g/ml toksik > 25

(56)



Efek yang tak diharapkan

 Mual, muntah, mulut kering, stomatitis  Penghambatan erythropoesis

 Gray syndrom

 Neuropati perifer  Anemi hemolitik

 Penekanan sumsum tulang, anemi aplastik

(t i a m f e n i k o l < kloramfenikol)

 Exantema, urtikaria, demam, gatal,

anafilaksi

 Kenaikan transaminase

(57)



Interaksi Obat

 Rifampicin menurunkan kadar plasma

 Paracetamol memperpanjang waktu paruh  Peningkatan efek obat antikoagulan oral,

antidiabetika oral, barbiturat, kodein, digitoxin, INH, methotrexat, fenitoin

(58)

Tetrasiklin



Bakteriostatik

berspektrum luas,



Khelasi dg Al, Fe,

Ca, Mg



Waktu paruh 5-10

jam, doksisiklin

12-24 jam

(59)

Makrolid (Eritromicin)



Eritromicin efektif mengatasi bakteri

gram + dan gram

_–

(neiseria

meningitidis, H Influenzae)



Alternatif untuk bakteri yang tahan

terhadap penisilin

(60)



Farmakokinetik

 Bioavailibility 70 %  VD 0,6 l/kg

 Ikatan protein plasma 80 %  Waktu paruh plasma 1,5 jam

 Eliminasi 15 % oleh renal tanpa diubah, 30

% bilier tanpa diubah, sisanya dimetabolisme dalam hati



Dosis 15-50 mg/kg/hr PO, IV 15-20

mg/kg/hr tiap 8-12 jam



Kadar terapeutik 1-2 g/ml setelah 500

mg PO, 12 g/ml 1 jam setelah injeksi 1

gIV

(61)



Efek yang tak diharapkan

 sakit dan tromboflebitis pd pemberian iv  Mual, muntah, sakit perut, mencret

 Peningkatan transaminase

 Fotosensibilitas: erytema, oedem,

pembentukan papula

 Jarang: aritmia kordis, ototoksisitas yang

reversible,

 Exantema, urtikaria, demam, eosinofilia,

(62)



Interaksi obat

 Meningkatkan konsentrasi teofilin

 Kombinasi ddg sulfonamid dicapai efek yg

kuat thd H influenzae

 Bakteriostatik menurunkan efek bakterisid

(misal penisilin)

 Terjadi resistensi silang dengan

(63)

Aminoglikosid



Sukar diabsorbsi saluran cerna



Bersifat ototoksik, nefrotoksik (hindari

pemakaian pd usia sangat muda dan

usila)



Streptomicin



Tx TBC, kombinasi dg

(64)



Farmakokinetik

 Bioavailibility: hanya untuk pemberian

parenteral

 VD: 0,25 l/kg

 Ikatan protein plasma 50 %  Waktu paruh 5 jam

 Eliminasi 40 % melalui renal tanpa diubah  Kadar terapeutik 15-40 mg/ml

(65)



Efek yang tak diharapkan

 Sakit tempat injeksi, pengerasan lokal  Nefrotoksisitas

 Ototoksisitas

 Blokade neuromuskuler  Reaksi alergi

 Jarang: anemia aplastik, sakit kepala,

neuropati perifer & okuler

 Kandungan Na-disulfit dan Na-sulfit 

(66)



Kanamisin, neomisin, framicetin,

paromomisin dapat digunakan sebagai

topikal injeksi pada sinovitis, pleuritis,

abses dan ijeksi sitemik untuk

bakteriemia, juga topikal krim, tetes

mata dan telinga

(67)



Gentamicin

Padar 2-10 g/ml

menghambat secara

invitro bbrp stain

stafilokokus, coliform

dan bakteri gram

negatif lainnya

Kebanyakan

(68)



Penggunaan klinik

 IV, IM -> sepsis, pneumonia yang resisten

thd obat lain

 Topikal: cream, ointment, solution  Intratekal: meningitis



Adverse reactions

 Nefrotoksis, Ototoksis  Jarang hipersensitif

(69)

Penggunaan antibiotika

_–

kemoterapetika

rasional



Kuratif (Ada infeksi)

Ada gejala & tanda yg umum

_–

patognomonis

Px lab. (kuman, lekositosis atau

lekopenia dan sebagainya

Hasil lab.

_

suseptibilitas kuman thd

antibiotik / kemoterapi tertentu

Pertimbangan kondisi penderita yg

mempengaruhi hasil terapi

(70)



Tx rasional berdasar Dx klinis

Gunakan obat yg diketahui pasti efektif

Jangan gunakan obat yg kurang efektif

Gunakan obat spektra sempit

Gunakan kombinasi obat



efek sinergis

Pantau efek samping (ototoksik

_–

aminogli

kosid, anemia aplastik

_–

kloramfenikol

dll.

Teruskan terapi sampai respon klinik

(71)



Tx profilaksi



resiko infeksi besar

Tindakan pembedahan

Seseorang yang masuk daerah

endemik infeksi tertentu

(72)

Tx irrasional

_

resistensi



Resistensi merupakan masalah yg

serius karena dengan semakin

banyaknya kuman yang resisten

terhadap antibiotika atau kemoterapi

berarti semakin sulit mengatasi infeksi

(73)

(74)

(75)

(76)



Mekanisme resistensi

 Inaktivasi antibiotik atau kemoterapi secara

enzimatik

 Substitusi (penggantian) lintasan

metabolisme

 Menimbulkan perubahan pada tempat obat

beraksi (site of action)

 Menimbulkan perubahan pada sistem

transport (uptake) antibiotik atau

(77)

(78)

(79)

 A. within the class of secondary active

transporters (symports, antiports, uniports): 4 superfamilies (comprising at least 10 families of gene products) including the SMR (Small Multidrug Resistance), the RND (Resistance Nodulation

Division), and the MFS (Major Facilitator Superfamily).

 B. within the class of primary active transporters

(energized by ATP):

at last 6 families of gene products including the PgP (in the MDR1 [Multiple Drug Resistance] group) and the MRP (Multiple Resistance Protein).

(80)

(81)

(82)



Antibiotic ~ (CNS, Respiratory Tract ,

Gastrointestinal Tract, Urinary Tract ,

Reproductive Sys., Soft

tissue)-Infections



Antibiotic ~ Microorganism

(Staphylococcus, Streptococcus, dll)

“Home work”