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Protein synthesis inhibitors: M.Sc. In Pharm (Pharmacology)

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Presentation on theme: "Protein synthesis inhibitors: M.Sc. In Pharm (Pharmacology)"— Presentation transcript:

1 Protein synthesis inhibitors: M.Sc. In Pharm (Pharmacology)
Chloramphenicol, Tetracyclines, Macrolides, Clindamycin Streptogramins & Oxazolidinones Pawitra Pulbutr, M.Sc. In Pharm (Pharmacology)

2 วัตถุประสงค์เชิงพฤติกรรม
เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ที่เกิดจากการใช้ยา, การนำไปใช้ประโยชน์ทางคลินิก รวมทั้งข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุ่ม Protein synthesis inhibitors ได้แก่ chloramphenicol, tetracyclines, macrolides, clindamycin, streptogramins, oxazolidinones, ketolides ได้

3 Bacterial protein synthesis

4 Drug acting as protein synthesis inhibitors
Chloramphenicol Tetracyclines Macrolides Clindamycin Ketolides Oxazolidinones Streptogramins Aminoglycosides Spectinomycin

5 Chloramphenicol First synthetic antibacterial Mechanism of action
Bind with 50s subunit Inhibit peptidyl transferase Inhibit transpeptidation … connection of peptide from P-site to A-site*** Bacteriostatic Bactericidal to some bacteria >>>H. influenzae, N. meningitidis, bacteroides Resistance Decrease uptake Chloramphenicol acetyl transferase enzyme… destroy

6 Clinical uses Serious rickettsial infection
Typhus … alternative to doxycycline Bacterial meningitis (due to PRSP, meningococcus) … alternative to penicillin Eye infection** .. Topical Melioidosis … Burkholderia pseudomalleri (gram negative rods)

7 ADRs GI disturbance.. n/v, diarrhea, oral-vaginal candidiasis
Bone marrow supression*** … dose dependent…> 50 mg/kg/day for 1-2 wks Aplastic anemia … idiosyncratic reaction… not dose dependent … 1 in 24,000-40,000 …. Fetal reaction Unexplained infection/ Bleeding/ Fatigue Toxicity for newborn Immature conjugation Gray baby syndrome … vomiting, flaccidity, hypothermia, gray color, shock, death Not > 50 mg/kg in infants , > 25 mg in immatures

8 Tetracyclines chlortetracycline oxytetracycline tetracycline
demeclocycline methacycline doxycycline minocycline Hydrochloride salt… more water soluble All chelates with divalent metal ions***

9 Mechanism of action Bind with 30 s subunit
Inhibit binding of aminoacyl-tRNA to A-site Inhibit protein synthesis Bacteriostatic

10 Spectrum Broad spectrum gram positive, negative, anaerobes rickettsiae
chlamydia mycoplasma protozoa (ameba, plasmodium)

11 Clinical uses DOC for Mycoplasma pneumonia, Chlamydia, Rickettsia infection Acne** Bronchitis Community acquired pneumonia Lyme disease Leptospirosis** Vibrio infection Atypical mycobacterial infection H. pyroli infection … Gastric ulcer Protozoal infection** … E. histolytica, Plasmodium (malaria)

12 Macrolides Macrocyclic lactone ring Erythromycin Roxithromycin
Clarithromycin Azithromycin

13 Mechanism of action Bind 50s subunit Inhibit aminoacyl translocation
Inhibit translocation of tRNA from A-site to P-site Resistance Decrease uptake or Efflux pump Produce esterase enzyme … destroy drugs Alteration of ribosomal binding site …. Methylase ***… MLS-B

14 Clinical uses DOC for … Corynebacterium infection (diphteria*, corynebacterial sepsis, erythasma) Respiratory, neonatal, ocular, genital Chlamydial infection* Community acquired pneumonia Pneumococci Mycoplasma Legionella

15 Many are resistant to macrolide too!!
Alternative to penicillin in.. streptococci staphylococci pneumococci pharyngitis skin & soft tissue infection pneumonia Many are resistant to macrolide too!! Endocarditis prevention in valvular heart disease pt undergoes dental surgery

16 Ketolides Telithromycin Macrolide like … macrocyclic lactone ring
3- keto group No L-cladinose sugar Macrolide like mechanism of action Bind to 50s subunit Higher affinity

17 Spectrum RTI caused by … beta-lactam, macrolide, tetracyclines, co-trimoxazole resistant bacteria S. pneumoniae H. influenzae M. catarrhalis Effective to MLS-B resistance*** No MLS-B inducer

18 Clindamycin Cl derivative of lincomycin
Erythromycin like mechanism of action… bind at 50 s subunit Erythromycin binding site Spectrum Streptococci Staphylococci Pneumococci Bacteroides & Other anaerobes*** Not effective to gram negative (poor permeability) , enterococci, Clostridium difficile

19 Streptogramins Quinupristin-dalfopristin (Synercid®)
Quinupristin = Streptogramin B 30% Dalfopristin = Streptogramin A 70% Macrolide like mechanism of action … bind at 50s subunit Spectrum Gram positive bacteria** Multidrug resistant streptococci Penicillin resistant pneumococci (PRSP)** MRSA** Enterococcus faecium (not E. faecalis) Not to gram negative***

20 Clinical uses …. IV infusion
Vancomycin resistant E. faecium (VRE) infection MRSA infection Streptococci infection Penicillin resistant/ susceptible pneumococci infection

21 Oxazolidinones Linezolid (Zyvox®) Mechanism of action Spectrum
Bind at 23s rRNA of 50s subunit Inhibit Ribosomal assembly Unique binding site … No cross resistance Time dependent killing Spectrum Gram positive which resistant to other drugs Staphylococci, Streptococci, Enterococci Gram positive anaerobes, rods MRSA,VRE, PRSP *** No activity on gram negative

22 Clinical use VRE infection Other multidrug resistant

23 Chloramphenicol bind at 50s
Tetracyclines Bind at 30s subunit Chloramphenicol bind at 50s Oxazolidinones … bind at 23s rRNA Macrolides/ Ketolides/ Clindamycin/ Streptogramins Bind at 50s subunit

24 THE END

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