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T etracyclines & Chloramphenicol

Chapter 42. T etracyclines & Chloramphenicol. Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn. 2013.12.26. Part A T etracyclines. Part A T etracyclines. Two classes: crude product Tetracycline( 四环素 )

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T etracyclines & Chloramphenicol

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  1. Chapter 42 Tetracyclines & Chloramphenicol Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University yunbi@zju.edu.cn 2013.12.26

  2. Part ATetracyclines

  3. Part ATetracyclines • Two classes: • crude product Tetracycline(四环素) Cholortetracycline (金霉素) Oxytetracycline (土霉素) • semisynthetic derivative Doxycycline(多西环素) Minocycline(米诺环素)

  4. General properties of Tetracyclines • Antimicrobial activity: • bacteriostatic • bactericidal (high concentration) • Minocycline > Doxycycline > Tetracycline

  5. General properties of Tetracyclines • “broad-spectrum” antibiotic • Rickattsiae (立克次体) • a number of aerobic and anaerobic G+ & G- bacteria • Chlamydia (衣原体) • Coxiella burnetii (螺旋体) • Mycoplasma pneumoniae (支原体) • Plasmodium(疟原虫) • not active against fungi, virus.

  6. General properties of Tetracyclines • Mechanism of action: Bind to 30S subunit of ribosome, preventing access of aminoacyl tRNA to acceptor (A) site on the mRNA-ribosome complex

  7. General properties of Tetracyclines • Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines

  8. General properties of Tetracyclines • Resistance Mechanism: (1) Decreased intracellular accumulation due to either impaired influx or increased efflux by a active transport protein pump. (2) Ribosome protection that interfere with the tetracycline binding to the ribosome. (3) Enzyme inactivation of tetracycline.

  9. General properties of Tetracyclines • ADME : (1) Absorption are impaired by food (except doxycycline and minocycline). (2) Distributed widely to tissue and body fluid except for CSF. • across the placenta and are also excreted in the milk. • tetracyclines are bound to- and damage- growing bones and teeth (chelation with calcium). (3) Excreted mainly in bile and urine.

  10. General properties of Tetracyclines • Clinical Uses (1) Rickettsial(立克次体) infections. (2) Mycoplasma(支原体) infections. (3) Chlamydia(衣原体) infection. (4) Leptospira(螺旋体) infection. (5) Bacterial infection.

  11. General properties of Tetracyclines • Adverse reactions (1) Gastrointestinal effects. (2) Superinfections. (3) Deposition of the drugs in growing teeth and bones. (4) Hepatic toxicity and renal toxicity. (5) Photosensitivity. (6) Vestibular toxicity (minocycline).

  12. Brown discoloration of teeth due to tetracycline exposure.

  13. Tetracyclinesagents • Tetracycline (四环素) • Doxycycline (多西环素) • Minocycline (米诺环素)

  14. Part B Chloramphenicol(氯霉素) p 1246 p776pharm Chemical structure

  15. Chloramphenicol 1. Antimicrobial activity: (1) a wide antimicrobial spectrum. (2) primarily bacteriostatic , may be bactericidal to certain species.

  16. Chloramphenicol 2. Mechanism of action Acts primarily by binding reversibly to the 50 S ribosomal subunit (near the site of action of macrolides and clindamycin, which it inhibits competitively).

  17. Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines

  18. Chloramphenicol 2. Mechanism of Resistance (1) a plasmid-encoded acetyltransferase that inactives the drugs (2) low permeability of bacterial cell membrane

  19. Chloramphenicol 3.Clinical uses (1) Bacterial meningitis， brain abscess. (2) Typhoid fever(伤寒) and other types of systemic Salmonella infections. (3) Eye bacterial infection. (4) Anaerobic infection. (5) Rickettsial disease and brucellosis, etc.

  20. Chloramphenicol 4. Adverse reactions (1)Hematological Toxicity: • dose-related toxic effect anemia, leukopenia, thrombocytopenia • idiosyncratic response aplastic anemia(再障), fatal pancytopenia(全血细胞减少症). (2) Gray baby syndrome. (3) hypersensitivty reaction, etc. 4. Drugs interactions inhibits Cy P450 enzyme mediated metabolism of warfarin, phenytoin, etc.

  21. Chapter 43 Synthetic antimicrobial agents

  22. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  23. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  24. From chloroquine to nalidixic acid

  25. 喹诺酮类(Quinolones) Generation Example time 1 Nalidixic acid 萘啶酸 1962 2 Pipemidic acid 吡哌酸 1973 3 Norfloxacin诺氟沙星 1980 4 Clinfloxacin 克林沙星 1990’s

  26. First generation fluoroquinolones (环丙沙星) (诺氟沙星) (培氟沙星) (氧氟沙星)

  27. From ofloxacin to levofloxacin

  28. Fluoroquinolones

  29. Fluoroquinolones • broad antimicrobial activity • effective after oral administration • relatively few side effects • resistance to their action does not develop rapidly.

  30. General properties of Quinolones 1. Antimicrobial activity & spectrum: (1) bactericidal and have significant PAE. (2) aerobic G- bacteria, Pseudomonas, aerobic G+bacteria, Chlamydia spp.（衣原体）, Legionella pneumophila(军团菌) , anaerobic bacteria, mycobacteria(分枝杆菌), multiple-resistance strains.

  31. DNA gyrase Topoisomerase Mechanism of action Key enzymes in DNA replication: bacterial DNA is supercoiled.

  32. porin DNA gyrase Topo isomerase Gram (-) Gram (+) Mechanism of action

  33. DNA gyrase Catalytic subunite Fluoroquinolones: 4 stacked molecules DNA gyrase ATP binding subunite Mechanism of action

  34. decreased permeability active efflux system porin DNA gyrase Topo isomerase mutation of the enzymes Gram (-) Gram (+) Mechanism of resistance

  35. ADME of fluoroquinolones • Absorption: well absorbed; bound by divalent cations • Do not administer with iron, magnesium, calcium • Distribution: all distribute widely (even in CSF), and most concentrate in urine • Metabolism: • hepatic metabolism diminishes the activity of norfloxacin and ciprofloxacin • Several have predominately hepatic clearance(Grepafloxacin格雷沙星, Sparfloxacin, Trovafloxacin曲伐沙星) • Excretion: urinary excretion predominates for the first generation fluoroquinolones

  36. ADME of fluoroquinolones

  37. Clinical Uses • Urinary tract infections. • GI and abdominal infections. • Respiratory tract infections. • Bone, joint and soft tissues infections, Osteomyelitis. • Meningitis • STD: Neisseria gonorrhea (奈瑟氏淋球菌)and Chlamydia (衣原体，Quinolone resistance in gonorrhea increasing)

  38. Adverse reactions • Gastrointestinal effects. • CNS side effects. • Allergic reaction. • Hepatotoxicity, nephrotoxicity. • Joint/cartilage toxicity, Tendinopathy • Achilles tendon rupture (跟腱断裂) • Limited FDA approval for children

  39. Fluoroquinolones agents • Norfloxacin(诺氟沙星) • Ciprofloxacin (环丙沙星) • Ofloxacin (氧氟沙星) • Levofloxacin (左氧氟沙星) • Lomefloxacin(洛美沙星) • Fleroxacin (氟罗沙星) • Sparfloxacin (司帕沙星) • Clinafloxacin (克林沙星) • Gatifloxacin (加替沙星)

  40. Contents • Quinolones ( 喹诺酮类) • Sulfonamides ( 磺胺类) • Other Synthetic antimicrobial Trimethoprim (甲氧苄啶) Nitrofurans (硝基呋喃类)

  41. Gerhard Domagk Nobel Laureate 1939 Inhibitors of Folate Synthesis 2,4-Diaminoazobenzen-4’-sulfonamide Prontosil (百浪多息)

  42. First Aid Packet carried by U.S. Soldiers in World War II http://home.att.net/~steinert/wwii.htm

  43. Sulfonamides (磺胺类) 对-氨基苯甲酸 Antimicrobial activity: • A wide antimicrobial spectrum. • Exerting onlybacteriostatic effect.

  44. Pteridine+PABA 蝶啶 二氢蝶酸 合成酶 Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid glutamate Dihydrofolic acid NADPH 二氢叶酸 还原酶 Dihydrofolate reductasease Blocked by trimethoprim NADP+ Tetrahydrofolic acid Mechanism of action

  45. Mechanism of Resistance • A lower affinity for sulfonamides by the dihydropteroate synthase • Decreased cell permeability or active efflux of the drug • An alternative pathway to synthesis the essential metabolites • An increased production of essential metabolites

  46. ADME of sulfonamides • Approximately 70%-100% of an oral dose is absorbed. • Distributing throughout all tissues of the body,even in CSF ( sulfadiazine 磺胺嘧啶 and sulfamethoxazole 磺胺甲噁唑, may be effective in meningeal infections) ;readily passing though the placenta. • Metabolized in the liver by acetylation.

  47. ADME of sulfonamides • Eliminated mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated may precipitate, thus induced renal disturbance.

  48. Clinical uses • Systemic infections. • Intestinal infections. • Infections of burn and wound.

  49. Adverse reactions • Urinary tract disturbances • Hypersensitivity reaction • Hematopoietic system disturbances • Kernicterus (胆红素脑病) • Hepatitis • GI effects Drugs interactions • All sulfonamides are bound in varying degree to plasma protein.

  50. Classification: • Oral absorbable agents • Short-acting agents • Medium-acting agents • Long-acting agents • Oral nonabsorbable agents • Topical agents • Combination agents

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