Protein Synthesis Inhibitors

1. Protein Synthesis Inhibitors Dr. Rajendra NathProfessor

2. Protein Synthesis Inhibitors& Other Newer Antibiotics 1)Protein Synth. Inhibitors that target the ribosome e.g.- -Tetracyclines - Chloramphenicol - Macrolide antb.s (Erythromycin) - Ketolide , Clindamycin (Lincosamides)

3. Protein Synthesis Inhibitors& Other Newer Antibiotics Streptogramins - Quinupristin / Dalfopristin Oxazolidinones– Linezolid 2) Comps. acting on cell membrane /cell wall : - Polymixin & Glycopeptides – e.g.- -Vancomycin & Teicoplanin

4. Protein Synthesis Inhibitors Lipopeptides – e.g. –Daptomycin. 3) Miscellaneous : Compds. acting by direct mech. e.g.- - Bacitracin - Mupirocin 4) Newer AM : Raptamulin Fidaxomycin

5. Protein Synthesis InhibitorsTetracyclines HISTORY : The development of the Tetracycline antibiotics was the result of a systemic screening of soil specimens collected from many parts of the world for antibiotic-producing micro-organism

6. Protein Synthesis InhibitorsTetracyclines • Chlortetracycline (prototype) is introducedin 1948 .( by S. aureofaciens ), followed by Oxy- tetracyclines & Tetracyclines in 1950 & 1952 respectively - Because of theiractionagainst G +ve , G- ve bact.s , Rikettsia ,Aerobes , An- aerobes & Chlamydia,they are known as Broad spectrum antibiotics .

7. Protein Synthesis InhibitorsTetracyclines

8. Protein Synthesis InhibitorsTetracyclines Source & Chemistry : -Oxytetracycline a natural product isolated from Streptomyces rimosus. -Tetracycline is semi synthetic derivative of Chlortetracycline ( isolated from Streptomyces aureofaciens ). -Others are Doxycycline & Minocycline - Tetracyclines are close cong.s of

9. Protein Synthesis InhibitorsTetracyclines polycyclic naphthocemecarboxamide having fusion of four cyclohexane rad. hence the name. OHO OH OCO – NH2 OH CH3 OHN(CH3)2

10. Protein Synthesis InhibitorsTetracyclines Susceptibility to micro-organisms(Spectrum) : Tetracyclines - more active against G +ve than G -ve micro- org.s. • G +ve: Staphylococci, Enterococi , & hemolytic Streptococi having variable susceptibility

11. Protein Synthesis InhibitorsTetracyclines G –ve: • B. anthracis & L. monocytogenes & H. influenzae are susceptible (Enterobacters have acquired resistance ) • Other Sensitive G –ve org.s are • Brucella - Helicobacter pylori • ,H. ducreyi ( Chancroid ) , - Yersinia pestis ( Plague) • V. cholerae - Enterocolitica • Legionella pnemophilla , - Tularemia • Campylobacter jejuni , - Pasteurella multocida

12. Protein Synthesis InhibitorsTetracyclines (strains of N. gonorrhea are no longer sensitive) . - Various anaerobes are also susceptible (e.g. – Bacterioides species , Propiono - bacterium & Pepcococcus ) -Tetracycline is active against Actinomyces & is DOC. -Rikettsia – All Tetracyclines are highly effective ( It causes Rocky mountain spotted fever ,Typhus, scrub typhus & Q – fever).

13. Protein Synthesis InhibitorsTetracyclines Miscellaneous : - Spirochetesincluding Borrelia recurrentis , Treponema pallidum ( Syphilis) , Chlamydia , - Mycoplasma -Non T.B. strains of Mycobacterium(e.g.-M.murium) - Amoeba & some atypical mycobacteria& Plasmodium species (but not active against Fungi ) .

14. Protein Synthesis InhibitorsTetracyclines Various Tetracyclines Used : -Tetracycline &Oxytetracycline -Chlortetracycline( obsolete in US ) -Minocycline & Doxycycline -Demeclocyclineareavailable. (Chlortetracyclines & Oxytetracyclines are used only in ophthalmic solution/ oint.)

15. Protein Synthesis InhibitorsTetracyclines • The more lipophylic drugs e.g.- Doxycyclines & Minocyclines usually are the most active followed by Tetracyclines . • Resistance to any one can cause cross resistance to others .

16. Protein Synthesis InhibitorsTetracyclines Effect on Intestinal Flora : Many of the Tetracyclines are incompletely absorbed from the GIT. & ↑ conc. in the bowel can markedly alter enteric flora. - Sensitive aerobic & anaerobic coliform micro-org. & G- ve spore forming bacteria are suppressed markedly.

17. Protein Synthesis InhibitorsTetracyclines As the fecal coliform count declines –overgrowth of Tetracyc. resist. micro-org.s occurs particularly- -Yeasts (esp. Candida sp.) - Enterococci - Proteus & - Pseudomonas

18. Protein Synthesis InhibitorsTetracyclines It occasionally produce Pseudomembranous Colitis ( caused by Clostridium difficile.) Mechanism of Action : Tetracyclines ↓ bact. protein synth. by binding to the 30s bact. ribosomes &prevent access of aminoacyl t-RNA – ribosome complex (by ↓its attachment to ‘A’ site)

19. Protein Synthesis InhibitorsTetracyclines

20. Protein Synthesis InhibitorsTetracyclines

21. Protein Synthesis InhibitorsTetracyclines

22. Protein Synthesis InhibitorsTetracyclines • They enter G -ve bact .by passive diff. through the hydrophilic channels formed by Porin protein of the outer cell memb. via the active transport energy dependent system. Resistance to Tetracycline : Plasmid mediated & is inducible .

23. Protein Synthesis InhibitorsTetracyclines Mech. of action of resistance: 1.↓ Accumul. of Tetracyc. as a result of either decreased antb. influx or acquisition of an energy dependant efflux pathway. 2. Prod. of ribosomal protective protein that displaces Tetracyc. from its target ( may occur by mutation ). 3. Enzymatic inactivation of Tetracyclines

24. Protein Synthesis InhibitorsTetracyclines Classification : 1. Incompletely absorbed ( 60-80% ) Natural- Oxytetra & Demeclocyc. Semi- synth. – Tetracyclines 2. Almost completely absorbed (90-100%) – Semi synthetic Doxycyclines & Minocyclines

25. Protein Synthesis InhibitorsTetracyclines Pharmacokinetics (Absorption , Distribution &Excretion) -Abs. of most Tetracyclines is incomplete. -% of oral dose that is absorb with empty stomach is : - Lowest for Chlortetracycline - Intermediate for Oxytetracyclines , Demeclocyclines & Tetracyclines - High for Doxycyclines (95%) & Minocyclines(100%)

26. Protein Synthesis InhibitorsTetracyclines Absorption of Tetracyc. is impaired by the concurrent ingestion of - Dairy prod. (milk & milk products ) - Aluminum hydroxide gel - Ca, Mg , iron & Zn salts and - Bismuth subsalicylate. ( food & dairy products do not interfere with the abs. of Doxy & Minocycline )

27. Protein Synthesis InhibitorsTetracyclines Half life ( t½ ) – Oxytetracyc. & Tetracyc. -6-12 hrs. Demeclocycline – 16 hrs. Doxycyc. & Minocyc. – 16-18 hrs.

28. Protein Synthesis InhibitorsTetracyclines Distribution : Widely distributed through out the body and into tissues & secretions including urine & prostate . They accumulate in RE cells of liver & spleen, bone marrow ,dentine & enamel of unerupted teeth .

29. Protein Synthesis InhibitorsTetracyclines • Penetration into most of the tissues & fluid is excellent e.g.- CSF. • It crosses the placenta & also secreted in milk .

30. Protein Synthesis InhibitorsTetracyclines Excretion : -Except Doxycycline the primary route of elimination for most of the Tetracyclines is the kidney ,also conc. in liver & excreted in bile( partly goes into enterohepatic circulation). - Excretion also occurs through feces even after the parenteral administration - Minocycline is metabolized in liver .

31. Protein Synthesis InhibitorsTetracyclines (Because of enterohepatic circulation these drugs may remain in the body for a long time after cessation of therapy). -Doxycycline at recommended doses does not accumulate significantly in pts with renal failure & thus is one of the safest of the Tetracyclines for use in patient with renal impairment .

32. Protein Synthesis InhibitorsTetracyclines Dose - wide variety of Tetracyclines are available for oral , parenteral & topical administration . Tetracycline- oral – 1-2 gm /day in adult( children -25 -50 mg/kg daily) in two-four div. doses . -Demeclocycline – 150 mg every 6 hrs used rarely as AM agent because it causes photosensitivity react. & nephrogenic diabetes insipidus .

33. Protein Synthesis InhibitorsTetracyclines - Doxycycline- 100 mg 12 hrly on 1st day then 100 mg OD (Child- 4-5 mg/kg/d on 1st day then 2-2.5 mg /kg OD. ) Parenteral : - Doxycycline – 200 mg I.V. infusion on 1st day then 100 mg once or twice subsequently -Tetracycline – in acute infections – 1 gm ( 2gm in severe inf. ) div. in equal doses . (Generally Tetracyclines should be given 2 hr. before or after meals ) Tetracyclines should not be given I.M. as local irritation & poor absorption occurs .

34. Protein Synthesis InhibitorsTetracyclines Local – except for local use in the eye topical use of Tetracycline is not recommended.

35. Protein Synthesis InhibitorsTetracyclines USES: 1.Rikettsial inf. ( DOC is Doxy ) Caused by obligate intracellular organism resembling viruses & bact. Maintained in nature by a cycle of animal reservoir & arthropod vector. They multiply in vas, endothelial cells & causes perivascular infiltr.& Leads to thrombosis , gangrene etc. Types are -Rocky mountain spotted fever -Epidemic & Scrub typhus -Q fever Tetracyclines are life saving & clinical improvement occurs in 24 hrs Others effective are Chloramphenicol .

36. Protein Synthesis InhibitorsTetracyclines 2. Mycoplasma inf. ( M. pneumonia) Mycoplasma is smallest living org. , lacks cell wall , do not synthesize Folic acid so naturally resist. to Sulfonamides .Erythromycin also effect. 3. Chlamydia– Lymphogranuloma –venereum (Doxy.- 100 mg BD x 21 days ) -Psittacosis & Trachoma –Doxy -100 mg BD x14 d . ( Trachoma is a type of follicular conjunctivitis & cause of blindness) . or Tetracycline in Trachoma – 250 mg QID x 14 days ( because it occurs in early childhood before complete calcification of the permanent teeth so is C/I ) .

37. Protein Synthesis InhibitorsTetracyclines 4. Non specific urethritis– Doxycycline – 100 mg BD. x 7 days . 5. Sexuallytransmitted diseases (STD): Not a DOC because of resistance. -C. Trachomatis is often a co-existent pathogen in acute PID including endometritis ,salpingitis & for peritonitis Doxy – 100 mg I.V. BD. followed by oral therapy x 7 days ( usually combine with Cefoxitin to cover anaerobes)

38. Protein Synthesis InhibitorsTetracyclines -Acute Epididymitis– single inj. of Ceftriaxone + Doxy 100 mg orally BD x 10 days ( Sexual partner with any of these diseases shall also be treated ) -Primary/ Secondary Syphilis- In non pregnant Penicillin resist. Pts can be treated with Tetracycline .

39. Protein Synthesis InhibitorsTetracyclines 6. Anthrax – Doxycycline – 100 mg 12 hrly ( 2.2 mg/kg in children ) x 60 days 7. Bacillary infections – -Brucellosis-Tetracycline + Rifampicin / Streptomycin is effective (caused by inf. milk of goat, cow or sheep & occurs in farmers ). -Tularemia-Although Streptomycin is preferred but Tetracyclines also are effective.

40. Protein Synthesis InhibitorsTetracyclines -Cholera– Doxy -300 mg single dose is effective in reducing stool volume & eradicating V. cholerae from stools with in 48 hrs ., but it is not a substitute for I.V. electrolytes & fluid replacement . - Shigellosis / Salmonella infection: The Tetracyclines are not effective because of resistance. ( but can be given in Traveller’s diarrhoea by E. coli )

41. Protein Synthesis InhibitorsTetracyclines 8. UTI – no longer recommended. 9. Other- Actinomycosis, Leptospirosis & infection by Borellia species (acute & prophylactic treatment of infections ) 10. Acne – Tetracyclines have been used to treat acne by inhibiting Propioni -bact. which reside in sebaceous follicles (low doses are used -250mg orally twice a day ).

42. Protein Synthesis InhibitorsTetracyclines 11. Amoebiasis – effective with other drugs. 12. Helicobacter pylori inf. of GIT ( peptic ulcer ) 13. Malaria caused by plasmodium.

43. Protein Synthesis InhibitorsTetracyclines Glycylcyclines The Glycylcyclines are synthetic analogs of the Tetracyclines; the Glycylcycline currently approved is Tigecycline, the 9-tert-butyl glycylamido derivative of Minocycline. -They display activity like older Tetracyc. & targetsTetracycline resistant org.s.

44. Protein Synthesis InhibitorsTetracyclines They are also active against - Methicillin Resist. S. aureus (MRSA) & S. epidermidis . - Penicillin resist. S. pneumoniae & - Vancomycin resist. enterococci (VRE) . (Tigecycline is not appreciably absorbed from the Gastrointestinal (GI) tract and is only available for parenteral administration)

45. Mnemonic : ( Uses) • T Tetracyclines are used for • E • T • R - Rickettsia ,Relapsing fever • A - Atypical pneumonia • C - Cholera • Y - LYme’s disease • C - Chlamydia • L - LGV • I - Inguinale ( granuloma ) • N • E - Epidemics of Plague

46. Protein Synthesis InhibitorsTetracyclines Side/ effects: • GIT -GI irritation most common after oral administration - Epigastric burning , - Nausea , Vomiting & Diarrhea - Esophagitis ( give drug with food ) . - Pseudomembranous colitis by Clostridia difficle .

47. Protein Synthesis InhibitorsTetracyclines 2. Photosensitivity – esp. by Doxy , & Demeclocycline 3. Hepatic toxicity :- (esp. during preg. on prolong use) 4. Renal toxicity : Tetracyc. have catabolic effect so aggravate azotemia (↑ blood urea) . Doxycycline is least nephro - toxic . (Demeclocycline often produce nephrogenic diabetes insipidus.)

48. Protein Synthesis InhibitorsTetracyclines Fanconi syndrome– characterized by nausea ,vomiting , polyuria, polydipsia, proteinuria , acidosis & glycosuria ,azotemia & kidney damage (due to formation of toxic metabolites e.g.-Epianhydrotetracycline & Epitetracycline which has been observed in pts ingesting outdated & degraded Tetracyclines) .

49. Protein Synthesis InhibitorsTetracyclines 5.Effectson teeth : Children may develop permanent brown discoloration of teeth ( the larger is the dose more intense the discolor.) (Total dose is more important & risk is more when given to neonates or babies before 1st dentition .)

50. Protein Synthesis InhibitorsTetracyclines the deposition of drug in teeth & bones is due to its chelating prop. & the formation of Tetra-calcium-orthophosphate complex . 6. Misce. : Tetracyclines are deposited in the skeleton during gestation & throughout childhood & may depress bone growth in Premature Infants .