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Tetracycline

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Tetracycline

  1. 1. TETRACYCLINES By: Pinili, Richelle Mae J. BSP3G
  2. 2. INTRODUCTION  Most important broad spectrum antibiotics  Obtained by: -Fermentation procedures from Streptomyces spp. -Chemical transformation of natural products  Derivatives of octahydronaphthacene- A hydrocarbon system that comprises four-annulated six-membered rings.  Amphoteric compounds
  3. 3. MECHANISM OF ACTION •Specific inhibitors of bacterial protein synthesis:
  4. 4. MECHANISMS OF RESISTANCE A.) Efflux mediated by transmembrane- spanning B.) Ribosomal protection C.) Enzymatic oxidation
  5. 5. GENERAL STRUCTURE General formula: 4-dimethyl amino- 1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a- pentahydroxy-6-methyl-1,11 dioxo-2- naphthacenecarboxamide
  6. 6. STRUCTURE-ACTIVITY RELATIONSHIP Positive effects: • The enolized tricarbonylmethane system at C- 1 to C-3 must be intact for good activity. • Aminoalkylation of the amide nitrogen yield derivatives that is more water soluble. (Rolitetracycline)
  7. 7.  Substituents at position 5,5a,6,7,8,9 (hydrophobic “northern and western” faces of the molecule).  More useful results have been achieved with the introduction of substituents at C-7.  6-position: most fruitful site for semisynthetic modification of the tetracyclines.
  8. 8. Negative effects: • All derivatives containing fewer than four rings are inactive or nearly inactive • Replacement of the amide at C-2 with other functions (aldehyde or nitrile) reduces or abolishes activity.
  9. 9.  Monoalkylation of the amide nitrogen reduces activity proportionately to the size of the alkyl group.  Removal of the 4-dimethylamino group reduces activity.  Activity is largely retained in the primary and N- methyl secondary amines but rapidly diminishes in the higher alkyl amines
  10. 10.  Esters of the C-12a hydroxyl group are inactive, with the exception of the formyl ester.  Alkylation at C-11a also leads to inactive compounds.  Dehydrogenation to form a double bond between C-5a and C-11a markedly decreases activity.
  11. 11. Retained effects: • 6-demethyl-6-deoxytetracycline- simplest tetracycline derivative that retains the characteristic broad-spectrum. • The integrity of substituents at Carbon atoms 1,2,3,4,10,11,11a and 12 (hydrophilic “southern and eastern”) cannot be violated drastically without deleterious effects on the antimicrobial properties of the resulting derivatives.
  12. 12. No effect: • Neither the 6a-methyl nor the 6B-hydroxyl group is essential for antibacterial activity.
  13. 13. PRODUCTS According to source: • Naturally occurring -Tetracycline -Chlortetracycline -Oxytetracycline -Demeclocycline • Semi-synthetic -Meclocycline -Methacycline -Minocycline -Rolitetracycline
  14. 14. According to duration of action
  15. 15. Short-acting: (half-life is 6-8hrs) Tetracycline  [4-dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro- 3,6,10,12,12a-pentahydroxy-6-methyl-1,11 dioxo-2- naphthacenecarboxamide]
  16. 16.  Chlortetracycline HCl  7-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,6,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide
  17. 17.  Oxytetracycline HCl  Chemical analog of chlortetracycline that showed similar antibiotic properties
  18. 18.  Intermediate acting: (half-life is 12hrs)  Methacycline HCl  6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride
  19. 19.  Demeclocycline  7-chloro-4-(dimethylamino)1,4,4a,5,5a,6,11,12a- octahydro-3,6,10,12,12a-pentahydroxyl,11-dioxo2- naphthacenecarboxamide
  20. 20.  Long acting: (half-life is 16hrs)  Doxycycline  α-6-deoxy-5-oxytetracycline
  21. 21.  Minocycline HCl  7-dimethylamino-6-demethyl-6-deoxytetracycline
  22. 22. CLINICAL USES Primary Uses:  Treatment for infections caused by: Mycoplasma pneumoniae Chlamydiae Ricketssiae Vibrios Spirochetes
  23. 23. Secondary Uses:  Alternative drugs in the treatment of syphilis  Treatment of respiratory infections caused by susceptible organisms  Treatment of leptospirosis  Treatment of acne  Prophylaxis against infection in chronic bronchitis
  24. 24.  Selective Uses:  Tetracycline  Treatment of gastrointestinal ulcers caused by Helicobacter pylori  Doxycycline  Lyme disease  Prevention of malaria  Treatment of amebiasis  Currently an alternative to macrolides in the initial of community-acquired pneumonia.  Minocycline  Meningococcal carrier state  Demeclocycline  Inhibits the renal actions of antidiuretic hormone(ADH)  Management of patients with ADH-secreting tumors
  25. 25. TOXICITY Gastrointestinal disturbances Bony structures and teeth Hepatic toxicity Renal toxicity Photosensitivity- Especially demeclocycline Vestibular toxicity- Doxycycline and Minocycline
  26. 26. TIGECYCLINE
  27. 27. • Glycylcycline antibiotic, a class of 9-dimethylglycylamino- (DMG)-substituted tetracyclines exemplified by DMG- minocycline(DMG-MINO),and DMG-6-methyl-6- deoxytetracycline (DMG-DMDOT)  Has a substitution at the D-9 position which is believed to confer broad spectrum activity.  A derivative of minocycline  IV use  Broad spectrum of action that includes organisms resistant to standard tetracyclines.
  28. 28.  Highly active against bacterial strains that exhibit tetracycline resistance.  Indications:  Complicated Intra-abdominal Infections  Complicated Skin Infections  Community-Acquired Pneumonia  Acute Myeloid Leukemia (Orphan)  Has similar side effects to the tetracyclines.

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