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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:
5 common chemical features they are
i. A macro cyclic lactone, usually having 12 to 17 atoms
ii. A ketone group
O
O
O
CH3
HO
H3C
CH3
CH3
OH3C
O
HO
CH3
N CH3
H3C
OH
H3C
CH3
OH
O
O
OH
O
H3CCH3
CH3
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:
O
O
O
CH3
HO
H3C
CH3
CH3
OH3C
OH
H3C
CH3
OH
O
Erythromycin
O
O
CH3
HO
H3C
CH3
OH3C
OH
H3C
CH3
O
Erythromycin 6,9-hemiketal
S1
S2
S1
S2
O
OHCH3
1 3
12
9
1 3
5
12 6
89
O
O
CH3
CH3
OH3C
CH3
O
S1
S2
O
CH3
1 3
12 6
89
O
H3C
HO
H3C
O
O
CH3
HO
H3C
CH3
OH3C
OH
H3C
CH3
O
8,9-Anhydroerythromycin 6,9-hemiketal
S1
S2
O
CH3
1 3
12 6
89
Anhydroerythromycin 6,9;9,12-spiroketal
H+
H
H3O+
-H3O+
H3O+
H+
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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 semi-synthetic 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 orallyErythromycin 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
O
O
CH3
HO
H3C
CH3
CH3
OH3C
O
HO
CH3
N CH3
H3C
OH
H3C
CH3
OH
O
O
OH
O
H3CCH3
CH3
Erythromycin
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Source: Isolated from streptomyces erythreus
Physical properties:Yellow to white crystalline powderSoluble in alcohol, slightly soluble in waterStable at neutral PH
Dosage forms:
Oral and topical dosage formsEnteric coted and delayed realese dosage
forms
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Drug interactions:AnticoagulantsBenzodiazepinesCyclosporineAntihistaminic drugsThese agents potentiate the action of erythromycin
Adverse effects:AbdominalcrampsEpigastric distress JaundiceTransient 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 erythromycinErythromycin ethylsuccinate Prodrug with more lipophilicity- longer duration of
actionErythromycin estolate
A lipid soluble,acid stable prodrug with better oral absorption
Erythromycin gluceptate A water-soluble salt of glucoheptanoic acid for
parentral dosage formsErythromycin lactobionate Erythromycin salt meant for parentral usage
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Clarithromycin
Clarithromycin
Semisynthetic derivative of erythromycin obtained by selective methylation at c-6
position: 6-Methyl ether of erythromycin
O
O
O
CH3
HO
H3C
CH3
CH3
OH3C
OH
H3C
O
O
OHO
CH3
N
CH3
CH3
O OH
CH3
CH3
OH
1 3
5
9
12
1`
1``
Clarithromycin
H3C
CH3
6
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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
• Nitrogen containing
15-membered lactone ring macrolides(azalides)
• Stable under acidic conditions, because it doesn’t form cyclic ketal.
O
O
CH3
HO
H3C
CH3
OH3C
OH
CH3
OH
O
OHO
CH3
N
CH3
CH3
O OH
CH3
CH3
OCH3
1 3
5
12
1`
1``
NCH3H3C
H3C
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. 22Visit www.bpharmstuf.com
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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