Protein Synthesis Inhibitors

1. Protein Synthesis Inhibitors BY S.Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences

2. Protein Synthesis Inhibitors • Tetracyclines • Amimoglycosides • Macrolides • Clindamycin • Chloramphenicol • Streptogramines • Oxazolidinones

4. Tetracycline • First compound, chlortetracycline introduced in 1948 • Highly effective against rickettsiae, gm + and – bacteria, chlamydia • Inhibit protein synthesis by reversibly binding to 30 S subunit of bacterial ribosome, preventing binding of aminoacyl tRNA to mRNA ribosomal complex • Bacteriostatic

5. Chemical Structure

6. Chemical Structure

7. Inhibition of bacterial protein synthesis by tetracyclines.

8. Resistance • Wide resistance limits clinical uses • Most penicillinase-producing staphylococci are resistant

9. Absorption • Incomplete GI absorption: tetracycline (60-80%), doxycycline (95%), minocycline (100%) • Dairy foods decrease absorption by forming nonabsorbable chelates with calcium ions; also Mg, Fe, Al (antacids)

11. Distribution • Widely distributed in body • Bind in tissues undergoing calcification (teeth, bones) or tumors with high calcium content (gastric carcinoma) • All cross placenta and concentrate in fetal bones and teeth • Minocycline best CSF penetration • Concentrated in saliva and gingival fluid

12. Excretion • Concentrate in liver and partially metabolized • Secreted into bile and excreted in urine • Doxycycline and minocycline largely excreted in feces • Use in renal insufficiency

13. General Therapeutic Uses • Lyme disease • Spirochete (Borelia burgdorferi) tick bite • Skin lesions, headache, fever, meningioencephalitis, arthritis • Mycoplasma pneumonia • Young adult pneumonia • Rocky mountain spotted fever • Fever, chills, bone and joint aches • Acne

14. General Therapeutic Uses • Chlamydia • Lymphogranuloma venereum- lymph node hypertrophy, obstruction, elephantiasis • Psittacosis- pneumonia, hepatitis, myocarditis, coma • Cholera • Ingested fecally contaminated food or water • Organism multiplies in GI tract and secretes enterotoxin producing diarrhea • Doxycycline reduces organism • Fluid replacement

15. Adverse Effects • GI discomfort • Anorexia, epigastric pain, abdominal distention, nausea, vomiting, diarrhea, sore mouth, perianal irritation • Hepatic injury • Increased during pregnancy • Nephrotoxicity

16. Adverse Effects • Teeth • Discoloration enamel and hypoplasia of teeth • Depression of bone growth • Deposition in fetal and growing bones, stunted growth • Photosensitization • Severe sunburn in sun; doxy/demeclocycline • Superinfections • Candida or GI staphylococcus

17. Contraindications • Pregnancy • Children • Renal insufficiency • Can use doxycycline

18. Drug Interactions • Do not give with other antibiotics unless establish synergy • Increased effects of anticoagulants • Not absorbed by cations like Ca, Mg, Fe, Al • H2 blockers may depress tetracycline uptake

19. Aminoglycosides • Contain amino sugars linked to aminocyclitol by glycosidic bonds • Binds to 30 S ribosomal subunit (streptomycin) or 50 S (gent/others), interfering with assembly of functional ribosomal apparatus or misreading of genetic code • Aerobic gram negative bacteria • Bactericidal or static

26. Resistance • Decreased uptake • Absent oxygen-dependent transport • Altered receptor • 30S ribosomal subunit binding site has lower affinity for aminoglycosides • Enzymatic modification • Plasmid R factors that synthesize enzymes to modify and inactivate antibiotic

27. Administration • Inadequate absorption when oral • All parenteral, except neomycin • Neomycin • Severe nephrotoxicity • Only topical use to reduce intestinal bacteria

28. Distribution • Good body fluid penetration, except CSF • Accumulation in renal cortex and inner ear lymph • All cross placenta

29. Metabolism • Rapidly excreted into urine • Alter dose in renal insufficiency

30. General Therapeutic Uses • Streptomycin • Bacterial endocarditis (+ Pen) • Tuberculosis (combination) • Tularemia- hunters skinning infected animals • Gentamycin: combination with Pen/Ceph • Urinary tract infections (E coli, enterobacter) • Pneumonia (pseudomonas, E coli, kleb) • Meningitis • Peritonitis

31. General Therapeutic Uses • Tobramycin • Same as gentamycin • Poor activity against enterococci • Amikacin • Initial treatment of serious nosocomial gram negative bacilli infections when resistance to gentamycin and tobramycin

32. General Therapeutic Uses • Netilmicin • Serious infections with enterobacteriaceae and other aerobic gram negative bacilli • Kanamycin • Few indications • Neomycin • Topical skin and mucosa infections

33. Adverse Effects • Ototoxicity • High peak levels and long duration • Nephrotoxicity • Neuromuscular paralysis • Intraperitoneal/intrapleural high dose; myasthenia gravis patients at risk • Contact dermatitis- neomycin topical • Monitor peak and trough plasma levels

34. Macrolides • Many membered lactone ring where sugars or amino acids are attached • Erythromycin • Azithromycin • Clarithromycin- more strep and staph • Dirithromycin • Troleandomycin • Telithromycin

36. Mechanism of Action • Bind to 50 S subunit of bacterial ribosome, inhibiting translocation step of protein synthesis • Bacteriostatic activity • Better intracellular concentration with gram + bacteria • Clarithro and Azithro more anaerobic

37. Inhibition of bacterial protein synthesis by the macrolide antibiotics erythromycin, clarithromycin, and azithromycin

38. Resistance • Inability of organism to take up antibiotic • Decreased affinity of binding site for antibiotic

39. Administration • Adequate oral absorption • Intravenous: thrombophlebitis • Intramuscular: painful

40. Distribution • Well into body fluids, except CSF • Diffuses into prostatic fluids • Accumulates in macrophages • Concentrated in liver • Penetrate well into abscesses

41. Metabolism • Inhibits oxidation of other drugs through interaction with cytochrome P-450 system

43. Excretion • Concentrated and excreted in an active form in the bile • Partial reabsorption through enterohepatic circulation

44. General Therapeutic Uses • Mycoplasma pneumonia • Syphilis- in penicillin allergic • Chlamydia- alternative to tetracycline; during pregnancy • Legionellosis pneumonia • Corynebacterium diptheriae- carriers • Ureaplasma- urethritis

45. General Therapeutic Uses • Alternative to penicillin in allergic patients • Clarithromycin (Biaxin) and Azythromycin (Zithromax) • COPD, pneumonia • Pharyngitis, tonsillitis • Acute maxillary sinusitis • Lower respiratory tract infections

46. Adverse Effects • Epigastric distress • Nausea, vomiting, pain, diarrhea • Cholestatic jaundice • When estolate form is used • Ototoxicity • High doses

47. Interactions • Increases plasma concentration of digoxin • Inhibits hepatic metabolism of drugs • Theophylin • Warfarin • Carbamazepine • Cyclosporin • Methylprednisolone • Terfenadine • Do not use in liver disease patients

48. Clindamycin • Introduced in 1970 • Semisynthetic derivative of lincomycin, isolated from soil near Lincoln, Nebraska in 1965 • Clindamycin produced by exchange of hydroxyl group with chlorine atom at C7 of lincomycin molecule

50. Clindamycin • Binds to 50 S subunit of bacterial ribosomes to inhibit protein synthesis • Bacteriostatic activity, but cidal action against susceptible organisms in vivo