MACROLIDES

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INTRODUCTION: 
Macrolide antibiotics are so named as they possess a macrocyclic lactone usually having 12 to 17 atoms  SOURCE: These are produced by streptomyces species and the products of actinomycetes
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Common Structural Features:
O

5 common chemical features they are i. A macro cyclic lactone, usually having 12 to 17 atoms ii. A ketone group

H3C HO H3C OH H3C O CH3 O CH3 O

CH3 H3C OH CH3 HO N CH3

O O CH3 O

O H3 C CH3 CH3 OH

Erythromycin

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iii. One or two aminosugars linked to the nucleus. iv. A Neutral sugar linked either to amino sugar or to lactone ring v. The presence of the dimethyl amino moiety on the sugar residue, which explains the basicity of these compounds and consequently formation salts.

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SPECTRUM OF ACTIVITY: 
active against most species of gram They are generally (+) bacteria both cocci and bacilli.  The antibacterial spectrum of activity of the more potent macrolides resembles that of pencillin.  They also exhibit useful effectiveness against gram(-)cocci, specially Neisseria Species

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MECHANISM OF ACTION:

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PHYSICAL PROPERTIES: 
Occurs as crystalline powders.  Water insoluble molecules.  stable in aqueous solutions at or below room temperature.  Unstable in acidic conditions and forms internal cyclic ketal.

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CHEMICAL PROPERTIES: 
Macrolides are stable in aqueous solutions at or below room temperature. Macrolides are unstable under acidic conditions &undergo an intramolecular reactions to form an inactive cyclic ketone.

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Chemical Instability Of Macrolides:
H
+

O OH H 3C HO H 3C OH H 3C O CH CH OH CH
3

CH

3

9

3

H 3C

H

9
HO

8 O
CH
3

12

H 3O
S1

+

H 3C

12

OH H 3C O

6
S1 O

5
O

1
3

3
O CH
3

CH

1
3

3
O CH
3

O

O

S2

S

2

E r y th r o m y c in

E r y th r o m y cin 6 ,9 -h e m ik e t a l
-H 3O
+

H 3C

CH

3

CH H 3C

3

H

+

HO

9
O

8
HO

9
CH
3

8 O
CH
3

O 6

H 3C

12
H 3C O

H 3O
S1 O

+

H 3C

12

OH H 3C O

6
S O
1

CH

1
3

3
O CH
3

CH

1
3

3
O CH
3

O

O

S

2

S2

A n h y d r o e r y t h r o m y c in 6 ,9 ; 9 , 1 2 - s p i r o k e t a l

8 ,9 -A n h y d r o e r y t h r o m y c in 6 ,9 - h e m ik e ta l

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STRUCTURAL ACTIVITY RELATIONSHIP 

As macrolide are unstable in acidic pH,a no. of strategies have been utilised to improve the acidic stability of erythromycin.  The addition of hydroxylamine to the ketone to form oxime e.g. roxithromycin

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alteration of c-6 hydroxyl group: nucleophilic functionality which initiates erythromycin degradation.  The azalides (azithromycin) are semisynthetic 15-membered congeners in which a nitrogen atom has been introduced to expand a 14-membered precursor- leads to an extended spectrum of action.

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PHARMACOKINETIC ASPECTS: 
These are administered orally  Erythromycin can also be given parenterally, through intravenous injections.  These diffuse readily into most tissues but do not cross the BBB & poor penetration into synovial fluid.

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Therapeutic Agents Of Macrolides: Erythromycin:
O H 3C HO H 3C OH H 3C O CH 3 O CH 3 O O H 3C CH 3 CH 3 OH O CH 3 H 3C OH CH 3 HO N CH 3

O O CH 3

Eryt romyci

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Source: 
Isolated from streptomyces erythreus

Physical properties: 
Yellow to white crystalline powder  Soluble in alcohol, slightly soluble in water  Stable at neutral PH

Dosage forms: 
Oral and topical dosage forms  Enteric coted and delayed realese dosage forms
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Drug interactions: 
Anticoagulants  Benzodiazepines  Cyclosporine  Antihistaminic drugs These agents potentiate the action of erythromycin

Adverse effects: 
Abdominalcramps  Epigastric distress  Jaundice  Transient deafness
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USES: It is used to treat 
The upper part of the respiratory tract infections, Mycoplasma pneumonia Gonorrhoea.  It is a good choice for penicillin-sensitive cases
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Therapeutic agents of erythromycin 
Erythromycin ethylsuccinate Prodrug with more lipophilicity- longer duration of action  Erythromycin estolate A lipid soluble,acid stable prodrug with better oral absorption  Erythromycin gluceptate A water-soluble salt of glucoheptanoic acid for parentral dosage forms  Erythromycin lactobionate Erythromycin salt meant for parentral usage
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Clarithromycin
9
   
C

C

12
C

6 5 1` 3
 
C

1

Semisynthetic derivative of erythromycin obtained by selective methylation at c-6 position: 6-Methyl ether of erythromycin
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Clarithromycin

C

 

 

 

H3C

C

1``
C

 

 
CH3 C C

C

C

   

Advantages: 
Cannot undergo cyclic ketal formation, so doesn¶t cause cramp in GI.  Higher blood concentrations.  More lipophyl.  Lower doses with less intervals USES: Effective against ‡Borrelia burgdorferi, ‡mycobacterium aviumcomplex
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Azithromycin
H3C

‡ Nitrogen containing 15-membered lactone ring macrolides(azalides) ‡ Stable under acidic conditions, because it doesn¶t form cyclic ketal.

N H3 C HO H3 C OH

CH3 CH3 CH3 N HO H3 C

12

OH

5
O

O

CH3 CH3

O CH3 O CH3

1`

1

3
O OCH3

1``
O CH3 OH CH3

Azithromycin

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USES:
‡ In the treatment of urogenital infections caused by N. gonorrhoeae and Chlamydia trachomatis. ‡ Widely prescribed for the treatment of respiratory tract infections. ‡ More active against gram(-)bacteria.

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ROXITHROMYCIN: 

Semi-synthetic 14-membered ring macrolide antibiotic in which the erythronolide lactone ring has been altered to prevent inactivation in the milieu.
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USES:
Active against both gram(+) & gram(-) 

Treatment of skin, dental and genital infections  Treatment of upper and lower respiratory tract infections.

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REFERENCES: 
S.N.Pandeya,Textbook of medicinal chemistry  Rama Rao Nadendla,Medicinal chemistry  Sri Ram, Medicinal chemistry  The Mechanism of Action of Macrolides, and Lovmar and Måns Ehrenberg .  Keicho N, Kudoh S (2002). "Diffuse panbronchiolitis: role of macrolides .  Lopez-Boado YS, Rubin BK (2008). "Macrolides as immunomodulatory therapeutic agents. Curr Opin Pharmacol.
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