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FARMAKOLOGI OBAT

ANTIBIOTIK

Rina Wijayanti, M. Sc., Apt

Ideal Antimicrobial Agent

Soluble in body

Stable in body

Selectively toxic

Consistent Toxicity

Non-allergic

Bacterial resistance difficult to develop

Long shelf life

Reasonable cost

Terms/Concepts of Antimicrobial Agent

• Selective Toxicity

• Spectrum of Activity

• Mode of Action

• Side Effects

• Resistance

Selective Toxicity

• Concentration that eliminates pathogen

– Therapeutic dosage level

• Concentration that causes damage to host

– Toxic dosage level

• Chemotherapeutic index =

Maximum tolerable dose (per Kg body weight)

Minimum therapeutic dose (per Kg body weight)

PENGGOLONGAN ANTIBIOTIK

BERDASARKAN DAYA KERJANYA

• ZAT BAKTERISIDA, pada dosis biasa berkhasiat mematikan

kuman

1. Zat yang bekerja pada fase tumbuh (penisilin, sefalosporin,

polipeptida, rifampisin, asam nalidiksat, kuinolon)

2. Zat yang berkerja terhadap fase istirahat (aminoglikosida,

nitrofurantoin, INH, klotrimoksazol)

• ZAT BAKTERIOSTATIK, pada dosis biasa terutama

berkhasiat menghentikan pertumbuhan dan perbanyakan

kuman (Sulfonamida, kloramfenikol, tetrasiklin, makrolida,

linkomisin)

PENGGOLONGAN ANTIBIOTIK

BERDASARKAN Spectrum of Activity

• Range of microorganisms that are affected by agent

– Broad spectrum

• Wide range, e.g. both gram-pos & gram-neg

• Used when infective bacterial agent on is not precisely

identified

– Narrow spectrum

• Limited number, or specific group of bacteria

• Used to prevent development of resistance

• Less of an affect on normal bacterial flora

Antibiotic Spectrum

Obligate intracellular microorganisms

Chlamydia – tiny, non-motile, spherical bacteria

Rickettsia – small, non-motile, gram-negative bacteria

PENGGOLONGAN ANTIBIOTIK

BERDASARKAN MEKANISME AKSI

1. Cell Wall

2. Cell membrane

3. Protein synthesis

4. Nucleic Acid Synthesis

5. Antimetabolites

Some clinically important antibiotics

Antibiotic Producer organism Activity

Site or mode of

action

Penicillin Penicillium chrysogenum Gram-positive bacteria Wall synthesis

Bacitracin Bacillus subtilis Gram-positive bacteria Wall synthesis

Polymyxin B Bacillus polymyxa Gram-negative bacteria Cell membrane

Amphotericin B Streptomyces nodosus Fungi Cell membrane

Erythromycin Streptomyces erythreus Gram-positive bacteria Protein synthesis

Neomycin Streptomyces fradiae Broad spectrum Protein synthesis

Streptomycin Streptomyces griseus Gram-negative bacteria Protein synthesis

Tetracycline Streptomyces rimosus Broad spectrum Protein synthesis

Vancomycin Streptomyces orientalis Gram-positive bacteria Protein synthesis

Rifamycin Streptomyces mediterranei Tuberculosis Protein synthesis

• Bacteria have a high internal osmotic pressure

• Without a sturdy cell wall, this pressure will cause

membrane to burst

• Antibiotics can interfere with formation of the cell wall

• Results in cell death by cell bursting open

• Sintesa dinding sel terganggu sehingga dinding menjadi

kurang sempurna dan tidak tahan terhadap tekanan

osmotis dari plasma dengan akibat pecah - DISRUPTION: GANGGUAN -STURDY: KOKOH – BURST: PECAH -INTERFERE:

MENCAMPURI

Cell Wall Disruption - Antibacterial

• Penicillin has a 4-member ring

• “looks like” part of the cell wall to the cross-linking enzyme

• Penicillin competes with the normal cell wall component for the

cross-linking enzyme, i.e. competitive inhibition

• Prevents this enzyme from cross-linking cell wall

penicillin

Cell Wall

Penicillin structure

Penicillin

• Penicillin G is the natural penicillin

– Produced by Penicillium notatum

• Administered by injection

– because is degraded by stomach acids

• Rapidly absorbed into blood & rapidly excreted

• Used against: streptococcus, meningococcus, pneumonococcus, spirochetes, clostridia, aerobic gram-positive rods, some staphylococcus and gonococcus

• Active in urine; so used for urinary tract infections

• Generally nontoxic

• Problems

– Allergic reaction (~5% in adults)

– Bacterial resistance

Semi-synthetic Penicillins

• Add a side-chain to the penicillin structure

• Alters: mengubah

– Chemical characteristics

– Spectrum of activity

– Development of bacterial resistance

• Methicillin

– Penicillinase resistant

– resistance by an different mechanism developed

• Ampicillin

– broad spectrum ( gram-neg & gram-pos)

– acid resistant, i.e. oral administration

Cephalosporins

• Produced by fungi, Cephalosporium

• ring similar to penicillins

– so action similar to penicillins

• Originally for gram-positive cocci

• Used when

– infecting bacterial strain is reistant due to penicillinase

– when allergy or toxicity to penicillin present

• Broader spectrum

• few serious side effects

– Local irritation at injection site

– Nausea, vomiting, diarrhea

– Penicillin allergic persons can also be sensitive (~15%)

β-lactam Antibiotics

Cell Wall - Polypeptide Antibiotics

• Bacitracin

– Produced by Bacillus licheniformis

– Small polypeptide

– Inhibits cell wall formation

– Used on lesions & wounds because:

• Poorly absorbed in body

• Toxic to kidneys

• Vancomycin

– Streptomyces

– Very narrow spectrum

– Used against Staphylococcus that is resistant to penicillin

– Vancomycin resistance is now developing

luka

Luka tembak

dihasilkan

Cell Wall - Antimycobacterial

• Isoniazid (INH)

– Inhibits synthesis of mycolic acid in cell wall of Mycobacteria

• Tuberculosis

– Administered with other antibiotics to prevent development of

resistance

• Ethambutanol

– Inhibits incorporation of mycolic acid into cell wall

• Rifampin (inhibits mRNA synthesis)

– Hits alternative target in cell

mencegah

• Isoniazid Complications

– Competitive inhibitor of niacin & Vitamin B6

– Prevents enzymes from converting niacin or Vitamin B6

to useful molecules

– Often supplement patient’s diet with extra Niacin &

Vitamin B6 during treatment

MEMBRAN SEL

• Molekul lipoprotein dari membran plasma ( di

dalam dinding sel) dikacaukan sintesanya

sehingga menjadi lebih permeabel.

• Hasilnya zat-zat penting dari isi sel dapat

merembes keluar.

• Contoh : polipeptida dan polyen (nistatin,

amfoterisin) dan imidazol (mikonazol,

ketokonazol)

Aminoglikosida

• Streptomisin, neomisin

• Menghambat sintesis protein

• Berikatan dengan ribosom sub unit 30S dan

mengubah bentuknya sehingga terjadi

misreading informasi yang dibawa oleh

mRNA

• Penghambatan terjadi pada tahap elongasi

Makrolid

• Eritromisin, spiramisin

• Mengikat molekul sub unit 23S rRNA

• Menghambat tahap

translokasi

Quinolon

• Ciprofloxacin

• Menghambat DNA girase (topoisomerase II)

Golongan Sulfa

• Analog PABA

• Menghambat terbentuknya THF (carrier

karbon yang digunakan dalam sintesis A, G,

T dan M)

ANTIBIOTIKA APAKAH YANG PALING TEPAT ?

3. SELEKSI ANTIBIOTIK

FAKTOR ORGANISME

TERAPI EMPIRIK SEBELUM HASIL

TES MIKROBIOLOGI, KULTUR &

SENSTIVITAS

TEMPAT INFEKSI DITEMUKAN

EFEK OBAT PADA ORGANISME

MIC, MBC

RESISTENSI ANTIBIOTIK

FAKTOR PASIEN

BERATNYA INFEKSI

STATUS IMUN

FAKTOR FARMAKOKINETIK

RIWAYAT PENYAKIT

STATUS ALERGI

FAKTOR

FARMAKOGENETIK

FAKTOR ANTIBIOTIK

SPEKTRUM AKTIVITAS ANTIBIOTIK

DOSIS, RUTE,

FREKUENSI PEMBERIAN

FARMAKOKINETIK

EFEK SINERGISTIK

INTERAKSI OBAT

EFEK SAMPING

HARGA/BIAYA

13/10/2017 27