prof. dr. ravisankar
TRANSCRIPT
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BETA LACTAM ANTIBIOTICS
VIGNAN PHARMACY COLLEGE, Vadlamudi,Guntur ,(A.P)
Dr. P. Ravisankar M. Pharm., Ph.D.PROFESSOR and HOD
CONTENTS: BETA-LACTAM ANTIBIOTICS• Introduction• Historical Background• Classification PENCILLINS• Introduction• Classification• Structural Activity Relationship• Mechanism of Action CEPHALOSPORINS• Introduction• Classification• Mechanism of Action CARBAPENEMS• Introduction MONOBACTAMS• Introduction Key points Conclcsion VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR.
(A.P) 2
The name “Lactam” is given to cyclic amides and is analogous to
the name “Lactone” which is given to cyclic esters .
Antibiotics that contains the β-lactam (a four membered cyclic
amide) ring structure constitute the dominant class of agent
currently employed for the chemotherapy of bacterial infections.
β-lactam are the most widely used group of antibiotics available.
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INTRODUCTION
NO
The first synthetic β-Lactam was prepared
by HERMANN STAUDINGER in 1907
by reaction of the schiff base of aniline and
benzaldehyde with diphenylketone in a
cycloaddition.
Upto 1970, most β-Lactam research was
concerned with the penicillin and cephalosporin
groups, but since then a wide variety of structures have been
described.
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HISTROICAL BACKGROUND
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CLASSFICATION OF β-LACTAM ANTIBIOTICS
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
1 •Beta Lactam antibiotics are indicated for the prophylaxis and treatment of bacterial infections caused by susceptible organisms.
2 •Traditionally Beta Lactam antibiotics were mainly active only against gram positive bacteria
3 •The beta lactam antibiotics active against various gram negative organisms has increased their usefulness
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CLINICAL USES
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ADVERSEEFFECTS
fever
angioedema
nausea
dermatitis
erythemarashes
diarrhea
vomiting
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PENICILLINS: It is an antibiotic, discovered by Alexander Fleming(1881-1955) in 1928.
β-lactam antibiotics
It was isolated from fungus Penicillium notatum.
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Alexander Fleming
(Penicillium notatum)
Florey and Chain isolated penicillin by freeze drying and chromatography.
Penicillin was effective even when it is diluted up to 800 times.
Biological sources: Penicillium notatum, Penicillium chrysogenum
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Fleming’s famous petridish
Penicillium chrysogenum
BASIC STRUCTURE OF PENICILLIN:
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Acyl amino side chain
6-Amino penicillanic acid
HC
C N
HC
C
C
S
O
CH3
CH3
COO-
H
HNCR
O
Free carboxylate
Cis stereochemistry
Most reactive carbonyl groupSite of Penicillinase action
Basic chemistry:Beta lactum ring+Thiazolidine ring
Bicyclic ring system sysyem is essential
Variable group
Beta lactum ring
Thiazolidine ring
Methyl groups
Classification of Penicillins
Natural penicillins β- lactamase resistant penicillins
Aminopenicillins Carboxypenicillins Ureidopenicillins
-Penicillin G-Penicillin V
-Methicillin-Nafacillin-Isoxazolyl Penicillins
-Ampicillin-Amoxicillin
-Ticarcillin -Piperacillin-Mezlocillin-Azlocillin
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PENICILLIN G (BENZYL PENICILLIN)
Acid unstable.
Parenteral route.
Self destructive mechanism in its
structure because of influence of acyl side chain.
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N
S
CH3
CH3
COOH
O
HNCH2C
O
H H
H
PENICILLIN DERIVATIVES
PENICILLIN V
More acid stable than Penicillin G.
Administered by oral route.
Electron withdrawing group is present in
acyl side chain.
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N
S
CH3
CH3
COOH
O
HNCH2C
O
OH H
METHICILLIN:
Has no electron withdrawing group
on the side chain.
Acid sensitive and has to be injected.
Steric shields can be added to penicillins to
protect from penicillinase enzyme.
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N
S
CH3
CH3
COOH
O
HNC
O
H H
HCH3
CH3
ON
SNH
COOH
CH3
CH3
C
O
ISOXAZOLYL PENICILLINS
ON
CH3
R1
R2
R1 R2
Oxacillin H HCloxacillin Cl HDicloxacillin Cl Cl
Better penicillinase resistant agents have been developed.The isoxazolyl ring acts as the steric shield butIt is also electron-withdrawing giving the Structure acid stability.Flucloxacillin Cl F
Bulky and electronwithdrawing
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AMPICILLIN:
If hydrophilic groups like
(NH2, OH , COOH ) are attached
to the carbon that is α to the carbonyl group
on the side chain then α hydrophilic group aids
the passage of penicillins through porins of gram –ve bacteria.
Acid stable
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N
S
CH3
CH3
COOH
O
HNCH H
HC
O
H
NH2
AMOXICILLIN:
β hydroxy ampicillin.
Same spectrum of activity as that of penicillin G but more
active against gram–ve bacteria.
Acid resistant hence given orally.
Non toxic.
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N
S
CH3
CH3
COOH
O
HNCH H
HC
O
H
NH2
HO
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STRUCTURAL ACTIVITY RELATIONSHIP :
12
3
4
56
7
Bacteristatic
Antibiotics
Bactericidal
Penicillins
Inhibit the synthesis of peptidoglycon layer containing NAM &NAG
connected by penicillin binding proteins(PBP)
Acts on PBP and inhibits the synthesis of Peptidoglycon. VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 20
MECHANISM OF ACTION: Gram +ve Gram -ve
Cell membrane
Peptidoglycon cell wall
Lipopolysaccharide layer
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(Peptidoglycan cell wall)
N-acetylglucosamine
N-acetylmuramic acid
Transpeptidases locatedwithin the cell membraneare responsible for cross linking thePeptidoglycan chains
Transpeptidases(Penicillin Binding Proteins)
In order to make the rigid grid,
There is an enzyme called
Transpeptidase,which connects the Little peptide
strings perpendicular to the NAM and NAG chains.
Cell membrane
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(Cell membrane)
(Peptidoglycan cell wall)
Penicillin’s inactivatethe transpeptidase enzymeby covalently bondingto the serine residues within the active site.
Bonding is by acetylation
Transpeptidases(Penicillin Binding Proteins)
S
O
BETA LACTAMASE INHIBITORS:
Has negligible antibacterial activity.
Given with Penicillins which increases spectrum of activity.
Microbial resistance to beta lactam antibiotics.
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Beta lactamase
β lactam antibiotics β lactam antibiotics + β lactamase inhibitor
Contain β lactum ring Complex
Catalysing the β lactamases hydrolysis of β lactum ring Effectiveness of β lactamase is diminished INACTIVE COMPOUNDS
Enhances the activity of β lactam antibiotics
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Clavulanic acid:
Isolated from Streptomyces clavuligerus.
1st naturally occurring β lactam ring that was not fused to a ‘S’
containing ring.
Sulbactum:
β lactamase disabiling agent.
Prepared by partial chemical synthesis
from penicillins.
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N
O
O
H
COOH
H
H
OH
N
S
O COO-Na+
H
O
CH3
CH3
O
H
Tazobactum:
Co-administered with Piperacillin. Has little or no antibacterial activity.
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N
S
O COO-
O CH3
O
H
NN
N
Beta lactamase Inhibitors:
Available agents β-lactamase binding Potency
Clavulanic acid + + + + + +
Sulbactam + + + + + +
Tazobactam + + + + + + + +
USES:
Streptococcal infections
Pneumococcal infections
Meningococcal infections
Gonorrhoea
Syphilis
Diphtheria
TetanusTOXICITY:
Nausea ,Dizziness ,Head ache ,skin rashes ,Bronchospasm , vasculitis ,
inflammation of blood vessles .
Hypersensitivity or allergic reactions.27
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CEPHALOSPORINS
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
Cephalosporins are second major group of β-lactam ,broad spectrum,penicillanase resistant antibiotics
They were isolated from cultures of Cephalosporium acremonium by italian scientist Giuseppe Brotzu in 1945.
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)29
INTRODUCTION
In 1948, Abraham and his colleagues have isolated three principle
antibiotic components from cultures of fungus.
1964 ,the first semi synthetic cephalosporin i.e. cefalothin was launched in the Market by Eli Lilly and company.
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Cephalosporin PCephalosporin NCephalosporin C
CLASSFICATION OF CEPHALOSPORINS
FirstGeneration
SecondGeneration
ThirdGeneration
FourthGeneration
FifthGeneration
1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral 1.Parenteral Cephalothin Cefamycinc Cefotaxime Cefepime Ceftobiprole Cephaloridine Cefoxitin Ceftazidime Cefpirome Cefazolin Cefotitan Ceftriaxone Cefmetazole 2.Oral 2.Oral 2.Oral Cephalexin Cefachlor Cefixime (Keflex) Cefprozil Cefdinir Cephadroxil Ceftibuten (Durecef)
3.Oral & Parenteral Cephradine 31VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
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These drugs are very active against Gram-positive cocci (such as Pneumococci, Streptococci, and Staphylococci).
They do not cross BBB.
1ST Generation Cephalosporins:
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They have a greater gram-negative spectrum while retaining some activity against gram-positive bacteria. They are also more resistant to β-lactamase. No BBB Penetration.
2nd Generation Cephalosporins:
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Expanded Gram-negative coverage Able to cross the BBB. Anti-pseudomonal activity.
3rd Generation Cephalosporins:
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Zwitterionic compounds. Good affinity for the transpeptidase enzyme. Low affinity for some β-lactamases. Cross BBB and effective in meningitis.
4th Generation Cephalosporins:
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VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
CEFTOBIPROLE
Active against methicillin-resistant -Staphylococcus aureus penicillin-resistant - Streptococcus pneumoniae
5th Generation Cephalosporins:
STRUCTURE -ACTIVITY RELATIONSHIP:
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Basic chemistry:β-lactam ring+Dihydrothiazine ring
Variable group
Variable group7-Aminocephalosporanic acid
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Cephalosporins are bactericidal.
Cephalosporins and β-lactams bind to
PBPs(Penicillin Binding Proteins).
Some PBPs have transpeptidase activity.
Transpeptidase activity is essential in cell wall synthesis.
MECHANISM OF ACTION:
USES:
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VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
Adverse effects:Disulfiram- like effectNephrotoxicityBleedingAllergic reactionsPhlebitis
IMPETIGO CELLULITIS P.aeruginosaINFECTIONS
PNEUMONIA BACTERIAL MENINGITIS
Cephalosporins advantages over penicillins:
Increased acid stability compare to penicillins.
Most of the drugs have better absorption than penicillins.
Broad antimicrobial spectrum.
Increased activity against resistant microorganisms.
Decreased allergenicity.
Increased tolerence than penicillins.
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CARBAPENEMS
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
Carbapenems are a class of β-lactam antibiotics with a broad spectrum of
antibacterial activity.
They have a structure that renders them highly resistant to most
β-lactamases.
Carbapenem antibiotics were originally developed from the carbapenem
thienamycin, a naturally derived product of Streptomyces cattleya
Examples
Imipenem, Meropenem, Ertapenem
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VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
INTRODUCTION
IMIPENEM:
IMIPENEM has a wide spectrum with
good activity many gram negative rods
incluiding P.aeruginosa, gram positive organisms and anaerobes.
Imipenem is inactivated by dehydropeptidases in renal tubules,
result in low urinary concentrations.
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(Imipenem)
Carbapenems which tend to be more common with imipenem are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites
Excessive levels of imipenem in patients with renal failure may lead to seizures
Patients allergic to penicillins may be allergic to carbapenems.
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ADVERSE EFFECTS
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MONOBACTAMS
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INTRODUCTION
Monobactams are drugs with a monocyclic β-lactam ring.
They are relatively resistant to beta-lactamases and active aganist
Gram-negative rods (including Pseudomonas and Serratia). They have no activity against Gram-positive bacteria or anaerobes.
Examples
Aztreonam , Tigemonam.
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
AZTREONAM Aztreonam is given i.v.
The half-life is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate aztreonam
without reaction
47VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
(Aztreonam)
KEYPOINTS:
Penicillins have a bicyclic structure consisting of a β-lactam
ring fused to a Thiazolidine ring.
Penicillin can be made more resistant to acid conditions by
incorporating an electron withdrawing group into the acyl side
chain.
Broad spectrum activity is associated with the presence of an
α-hydrophilic group on the acyl side chain of penicillins.
Cephalosporins contain a strained β-lactam ring fused to a
dihydrothiazine ring.
Semi-synthetic cephalosporins can be prepared from
7- aminocephalosporanic acid.
Methyl substitution at the 3-position of cephalosporins is good
for oral absorption.VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P) 48
Beta lactam antibiotics are useful and frequently prescribed
antibiotics that share a common structure.
Bacterial resistance against the beta lactam antibiotics continues
to increase at a dramatic rate.
Therapy with beta lactam antibiotics is a dynamic that
prevalence of bacterial resistance to these agents continues to
rise, while new and more effective agent are released for clinical
use.49
VIGNAN PHARMACY COLLEGE, VADALAMUDI,GUNTUR. (A.P)
Conclusion:
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William O. Foye.,Textbook of Medicinal Chemistry,Pg no: 1089 -1106
Sriram., Medicinal Chemistry, Pg no: 295-309.
Kadam., Textbook of Medicinal Chemistry, Pg no: 68-82.
Ilango., Principles of Medicinal chemistry(vol.1), Pg no: 121-143.
G.L.Patrick., Introduction to Medicinal Chemistry, Pg no:388-415.
Good man And Gil Man’s ;The Pharmacology Basis Of Therapeutics
Tenth Edition page no 1189-1225.
JH Block & JM Beale., Wilson & Giswold’s Textbook of Organic
Medicinal Chemistry & pharmaceutical chemistry 11th Edition, 2004.
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Reference:
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