Jelaskan hubungan:
Jelaskan hubungan:
• • • •
• • • • •
Sulphonamide PABA Folate Bakteri vs. manusia ?
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Trimethoprim Tetrahydrofolate Thymidylate Dihydrofolate reductase Bakteri vs. manusia ?
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Target Kerja Antibakteri
ANTIBAKTERI
I. Enzim sintesis dinding sel II. Ribosom bakteri III. Enzim sintesis nukleotida dan replikasi DNA
(Target Kerja pada Ribosom dan Inti Sel Bakteri)
Dripa Sjabana, dr., M.Kes
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Mata Ajar Farmakologi Prodi Pendidikan Dokter Universitas Airlangga 2006
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Antibiotika dengan Target Kerja
Antibiotika dengan Target Kerja
Ribosom Bakteri 50S
Ribosom Bakteri 30S A. Tetracycline
A. Chloramphenicol B. Macrolide 1. 2. 3. 4.
1. 2. 3. 4. 5.
Erithromycin Clarithromycin Azithromycin Ketolide
Chlor- , oxy-, tetracycline Demeclocycline Methacycline Doxycyline minocycline
B. Aminoglycoside 1. 2. 3. 4.
C. Clindamycin (deriv. lincomycin) D. Streptogramin (quinupristin – dolfopristin) E. Oxazoladinone (linezolid)
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streptomycin neomycin, kanamycin, paramomycin gentamycin Amikacin, tobramycin, sisomicin, metilmicin, dll
C. Spectinomycin
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SITE OF ACTION OF
CHEMOTHERAPY IN BACTERIAL PROTEIN SYNTHESIS
Chloramphenicol
(1)
• Chloramphenicol, thiamphenicol Æ inhibisi transpeptidasi • Bakteriostatik Æ bakterisid • Pahit Æ + palmitat / stearat • Indikasi:
1 = chloramphenicol, 50S (inhibit peptidyl transferase) 2 = macrolides, clindamycin, type B streptogramins (block translocation) 3 = tetracyclines, 30S (block binding)
– Demam tifoid • Tetapi ciprofloxacin / amoxicillin / co-trimoxazole sama efektif dan kurang toksik.
– Meningitis purulenta – Infeksi anaerob
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Chloramphenicol
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(2)
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Chloramphenicol
• ESO hematologis:
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(3)
• Interaksi Obat:
– Depresi sumsum tulang – Anemia reversibel -idiosinkrasi
– Menghambat enzim mikrosom hati sehingga t½ obat lain diperpanjang (yang dimetabolisme di hati).
• SINDROMA GRAY – Sistem konjugasi belum sempurna, prematur, dosis >>, H2-9 terapi – Muntah Æ sakit berat, abu-abu, hipotermi – Kematian 40%
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Tetracycline
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Tetracycline
(1)
• Absorbsi: – – – –
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(2)
• Untuk menurunkan kejadian ESO:
30% chlortetracycline 60-70% t, oxy-t, demcloxycline, methacycline (t1/2 12j) 95-100% doxycline, minocycline (t1/2 16-18j) Diganggu oleh: • • • •
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Makanan (kecuali: doxyc dan minoc) Divalent cation (Ca2+, Mg2+, Fe2+ atau Al3+) Dairy products & antacids (multivalen) Alkaline pH
• Kompetisi dengan tRNA • Indikasi: kolera, GO, acne vulgaris
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– Jangan pada ibu hamil Kompleks: jar. tulang, disgenesis – Jangan pada anak – Doxycycline boleh untuk gagal ginjal – Hindari profilaksis – Sisa obat sebaiknya dibuang
SINDROMA FANCONI Poliuria, polidipsia, proteinuria, asidosis, glukosuria, aminosiduria, mual dan muntah 11
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Tetracycline pada Ibu Menyusui ?
Macrolide •
Erithromycin, clarithromycin, azithromycin, ketolide Æ inhibisi translokasi
• • • • •
Rusak oleh asam lambung Æ disalut Tidak menembus BBB ESO: jarang Spektrum: difteri, tetanus, sifilis Profilaksis:
• Farmakokinetik ? – Teoritis – Klinis
– demam reumatik – Cabut gigi +endokarditis bakteri
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Aminoglicoside
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Target Kerja Antibakteri
• Gentamycin, streptomycin, dll Æ abN codon • Gram (-) aerob • Penetrasi bakteri melalui transpor aktif yang dapat disakat (block) oleh chloramphenicol. • Resistensi akibat gagal penetrasi dapat diatasi dengan pemberian bersama penicillin &/atau vancomycin.
I. Enzim sintesis dinding sel II. Ribosom bakteri III. Enzim sintesis nukleotida dan replikasi DNA
• ESO: – Alergi – Iritasi dan toksik (oto & nefrotoksik)
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Antibiotika dengan Target Kerja
Enzim Sintesis Nukleotida & Replikasi DNA
Figure 45.1 Structures of two representative sulfonamides and trimethoprim. The structures illustrate the relationship between the sulfonamides and the p-aminobenzoic acid moiety in folic acid (orange box), and the possible relationship between the antifolate drugs and the pteridine moiety (orange). Cotrimoxazole is a mixture of sulfamethoxazole and trimethoprim.
A. Antifolat 1. Sulfonamide 2. trimethoprim
cotrimoxazole
B. Inhibitor DNA gyrase 1. Fluoroquinolone Ciprofloxacin, gatifloxacin, norfloxacin, ofloxacin, dll
2. Nalidixic acid, cinoxacin 3. novobiocin
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compete
Bacteria (+), human (-)
Figure 45.2 The action of sulfonamides and trimethoprim on bacterial folate synthesis.
Ciprofloxacin
Structural analogue PABA
• Spektrum luas • Absorpsi diganggu oleh antasida aluminium dan magnesium • Terkonsentrasi terutama pada ginjal, prostat, dan paru • Interaksi penting (inhibisi enzim P450) dengan theophylline Æ toxicity
Sensitivity: bacteria>human
Resemble the pteridine moiety of folate
See Figure 21.2 for more detail of tetrahydrofolate synthesis, and Table 44.1 for comparisons of antifolate drugs. (PABA, paminobenzoic acid.)
POTENTIATE Folate deficiency Æ megaloblastic anaemia ? Prevented by giving folinic acid.
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Figure 44.6 Schematic diagram of the action of DNA gyrase: the site of action for quinolone antibacterials. A Conventional diagram used to depict a bacterial cell and chromosome (e.g. Escherichia coli). Note that the E. coli chromosome is 1300 mm long and is contained in a cell envelope of 2 µm x 1 µm; this is approximately equivalent to a 50 m length of cotton folded into a matchbox. B Chromosome folded around RNA core, and C then supercoiled by DNA gyrase (topoisomerase II). Quinolone and antibacterials interfere with the action of this enzyme.
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Figure 45.4 A simplified diagram of the mechanism of action of the fluoroquinolones. A An example of a quinolone (the quinolone moiety is shown in orange). B Schematic diagram of (left) the double helix and (right) the double helix in supercoiled form. (See also Fig. 44.6.) In essence, the DNA gyrase unwinds the RNAinduced positive supercoil (not shown) and introduces a negative supercoil.
(Modified from: Smith J T 1985 In: Greenwood D, O'Grady F (eds) Scientific basis of antimicrobial therapy. Cambridge University Press, p. 69.)
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Apakah mungkin pemberian gentamycin 1 kali sehari ? Jelaskan !
Edukasi pasien • Perhatikan cara menyimpan: – Hindari sinar matahari ? – Hindari panas ?
• Farmakokinetika (t ½)? • Farmakodinamika antibakteri ?
• Cara minum obat: – 3 dd ? – Sesudah / sebelum makan ? – Durasi terapi ?
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Mengapa pemberian kombinasi tetracycline dan ampicillin tidak dianjurkan ?
Bacaan lanjut • Katzung BG ed.(2004). Farmakologi Dasar & Klinik, ed.8, buku 3. Jakarta: Salemba Medika, hal.37-88. • Rang HP et al. (2003). Pharmacology, ed.5. London: Elsevier, p.620-649.
• Farmakokinetika (interaksi) ? • Farmakodinamika antibakteri ?
Diskusi pada situs internet FK Unair di http://www.fk.unair.ac.id/forum Forum Prodi Dokter
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Insya Allah berjumpa pada pertemuan selanjutnya.
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