T etracyclines & Chloramphen etracyclines & Chloramphen icol icol Chapter 42 Chapter 42 Yun-Bi Lu, PhD Yun-Bi Lu, PhD 卢卢卢 卢卢卢 Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang University School of Medicine, Zhejiang University [email protected][email protected]2013.12.26
Chapter 42. T etracyclines & Chloramphenicol. Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]. 2013.12.26. Part A T etracyclines. Part A T etracyclines. Two classes: crude product Tetracycline( 四环素 ) - PowerPoint PPT Presentation
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• Rickattsiae Rickattsiae (( 立克次体立克次体 ))• a number of a number of aerobic and anaerobic aerobic and anaerobic GG++
& G& G-- bacteria bacteria • Chlamydia Chlamydia (( 衣原体衣原体 ))• Coxiella burnetii Coxiella burnetii (( 螺旋体螺旋体 ))• Mycoplasma pneumoniae Mycoplasma pneumoniae (( 支原体支原体 ) ) • PlasmodiumPlasmodium (( 疟原虫疟原虫 ))• not active against fungi, virus.not active against fungi, virus.
General properties of TetracyclinesGeneral properties of Tetracyclines
Mechanism of action:Mechanism of action: Bind to 30S subunit of ribosome,
preventing access of aminoacyl tRNA to acceptor (A) site on the mRNA-ribosome complex
General properties of TetracyclinesGeneral properties of Tetracyclines
General properties of TetracyclinesGeneral properties of Tetracyclines
Mechanism of action:Mechanism of action:
①①ChloramphenicolChloramphenicol
②②Macrolides, ClindMacrolides, Clindamycinamycin
③③TetracyclinesTetracyclines
Resistance Resistance Mechanism:Mechanism:
(1) Decreased intracellular (1) Decreased intracellular accumulation due to either impaired accumulation due to either impaired influx or increased efflux by a influx or increased efflux by a active active transport protein pumptransport protein pump..
(2) (2) Ribosome protectionRibosome protection that interfere that interfere with the tetracycline binding to the with the tetracycline binding to the ribosome.ribosome.
(3) (3) Enzyme inactivationEnzyme inactivation of tetracycline. of tetracycline.
General properties of TetracyclinesGeneral properties of Tetracyclines
ADADME :ME :
(1) (1) AAbsorption are impaired by food (except doxycycline bsorption are impaired by food (except doxycycline and minocycline).and minocycline).
(2) (2) DDistributed widely to tissue and body fluid except for istributed widely to tissue and body fluid except for CSF.CSF.
• across the placenta and are also excreted in the milk.across the placenta and are also excreted in the milk.
• tetracyclines are bound to- and damage- growing bontetracyclines are bound to- and damage- growing bones and teeth (chelation with calcium).es and teeth (chelation with calcium).
(3) (3) EExcreted mainly in bile and urine.xcreted mainly in bile and urine.
General properties of TetracyclinesGeneral properties of Tetracyclines
DNA gyraseDNA gyraseCatalytic subuniteCatalytic subunite
DNA gyraseDNA gyraseATP binding subuniteATP binding subunite
Mechanism of resistanceMechanism of resistance
Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase
Gram (-)Gram (-) Gram (+)Gram (+)
porinporin
mutation of mutation of the enzymesthe enzymes
active effluxactive effluxsystemsystem
decreaseddecreasedpermeabilitypermeability
• AAbsorption: well absorbed; bound by divalent cationsbsorption: well absorbed; bound by divalent cations– Do not administer with iron, magnesium, calciumDo not administer with iron, magnesium, calcium
• DDistribution: all distribute widely (istribution: all distribute widely (even in CSF)even in CSF), and , and most concentrate in urinemost concentrate in urine
• MMetabolism: etabolism: – hepatic metabolism diminishes the activity of norfloxacin hepatic metabolism diminishes the activity of norfloxacin
and ciprofloxacinand ciprofloxacin– Several have predominately hepatic clearanceSeveral have predominately hepatic clearance
• EExcretion: urinary excretion predominates for the first xcretion: urinary excretion predominates for the first generation generation fluoroquinolonesfluoroquinolones
First Aid Packet carried by U.S. Soldiers in World War II
http://home.att.net/~steinert/wwii.htm
Sulfonamides (Sulfonamides ( 磺胺类磺胺类 ))
Antimicrobial activity:Antimicrobial activity:• A wide antimicrobial spectrum.A wide antimicrobial spectrum.• Exerting onlyExerting only bacteriostatic effect.bacteriostatic effect.
对 - 氨基苯甲酸
Mechanism of actionMechanism of action
Pteridine+PABA
Blocked by sulfonamides
Dihydropteroic acid
Dihydrofolic acid
glutamate
Tetrahydrofolic acid
Blocked by trimethoprim
NADPH
NADP+
Dihydropteroatesynthase
Dihydrofolatereductasease
蝶啶
二氢蝶酸合成酶
二氢叶酸还原酶
Mechanism of ResistanceMechanism of Resistance • A lower affinityA lower affinity for sulfonamides by the dih for sulfonamides by the dih
ydropteroate synthaseydropteroate synthase• Decreased cell permeabilityDecreased cell permeability or active efflux or active efflux
of the drugof the drug• An alternative pathwayAn alternative pathway to synthesis the es to synthesis the es
sential metabolitessential metabolites• An increased productionAn increased production of essential meta of essential meta
bolitesbolites
ADME of sulfonamidesADME of sulfonamides
• AApproximately 70%-100% of an oral dose is approximately 70%-100% of an oral dose is absorbed.bsorbed.
• DDistributing throughout all tissues of the bodistributing throughout all tissues of the body,y, even ineven in CSF CSF ( sulfadiazine ( sulfadiazine 磺胺嘧啶 磺胺嘧啶 and sand sulfamethoxazole ulfamethoxazole 磺胺甲噁唑磺胺甲噁唑 , may be effectiv, may be effective in meningeal infections) ;readily passing the in meningeal infections) ;readily passing though ough the placentathe placenta..
• MMetabolized etabolized in the liverin the liver by acetylation. by acetylation.
ADME of sulfonamidesADME of sulfonamides
• EEliminated mainly liminated mainly in the urinein the urine as the as the unchanged drug and metabolic unchanged drug and metabolic product. In acid urine, the eliminated product. In acid urine, the eliminated may precipitate, thus induced may precipitate, thus induced renal renal disturbance. disturbance.
Clinical usesClinical uses
• Systemic infections.Systemic infections.
• Intestinal Intestinal infections.infections.
• Infections of burn and wound.Infections of burn and wound.
Adverse reactionsAdverse reactions• Urinary tract disturbancesUrinary tract disturbances• Hypersensitivity reactionHypersensitivity reaction• Hematopoietic system disturbancesHematopoietic system disturbances• Kernicterus (Kernicterus ( 胆红素脑病胆红素脑病 ))• HepatitisHepatitis• GI effectsGI effects
Drugs interactionsDrugs interactions• All sulfonamides are bound in varying deAll sulfonamides are bound in varying de
1) Features 1) Features • TrimethoprimTrimethoprim(( 甲氧苄啶甲氧苄啶 )) in combination in combination
with Sulfamethoxazole(1:5) exertswith Sulfamethoxazole(1:5) exerts a a synesynergistic effectsrgistic effects. .
• The ADME of the two agents is similar.The ADME of the two agents is similar.• Co-block essential enzymes ofCo-block essential enzymes of folate mefolate me
tabolism. tabolism.
Pteridine+PABA
Blocked by sulfonamides
Dihydropteroic acid
Dihydrofolic acid
glutamate
Tetrahydrofolic acid
Blocked by trimethoprim
NADPH
NADP+
Dihydropteroatesynthase
Dihydrofolatereductasease
2)Clinical Uses 2)Clinical Uses
• Chronic and recurrent infections in the urinChronic and recurrent infections in the urinary tractary tract
• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (e.g. induced by GI infections (e.g. induced by SalmonellaSalmonella))• pneumocystis carinii pneumocystis carinii pneumoniapneumonia ( ( 肺囊虫性肺囊虫性
肺炎肺炎 ))
3)Adverse reactions
• There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.
• Hypersensitive reactions• GI effects• The effects of HIV patients• Drug interactions: warfarin, phenytoin
• Trimethoprim Trimethoprim (( 甲氧苄啶甲氧苄啶 ))
• Nitrofurans Nitrofurans (( 硝基呋喃类硝基呋喃类 ))
NitrofurantoinNitrofurantoin(( 呋喃妥因呋喃妥因 ))
Other Other SyntheticSynthetic antimicrobial antimicrobial