CEPHALOSPORINS

Introduced

in recent years for clinical use. The first agent, Cephalosporin C exhibited low antibacterial activity. Adding different substrates to produce other Cephalosporins did not work. But then using 7- ACA (7-amino cephalosporinac acid) produced enzymatically or chemically, lead to the production of very useful drugs with broad spectrum and resistance to -lactamases.

Cephalosporin C

7-Amino cephalosporanic acid (7-ACA)

CEPHALOSPORINS
Grouped

into generations according to their effectiveness against different organisms, their characteristics, and their development (first through fourth generation).

CEPHALOSPORINS
Cephalosporins

shares many of Penicillins properties, including mechanism of action, toxicity...etc. A person who has a reaction to penicillin may also have a reaction to cephalosporins.

CEPHALOSPORINS
In

general, Cephalosporins are more resistant to -lactamases and have a broader spectrum. However Penicillins are more potent against non -lactamase producing bacteria .

 The

presence of the sex-member ring dihydrothiazine instead of the five-member thiazolidene ring in Penicillin will mean that the -lactam ring is under less stress so it will be less susceptible to act as a substrate for PBP.

Structure Activity Relationship

Changes in R-1 may cause changes in spectrum and -lactamase resistance, similar to Penicillins. [An electron withdrawing group will give the compound better acid stability, a bulky group close to the ring, gives it better resistance to -lactamases and a polar group extends its spectrum].

Structure Activity Relationship

Structure Activity Relationship

Structure Activity Relationship

Structure Activity Relationship

Changes in R-2 will affect the pharmacokinetic properties of the drug.

Structure Activity Relationship

Addition of a methoxy group at the 7-alpha position lead to compounds that are very effective against -lactamase producing organisms.

Methoxy group at 7-position

CEPHALOSPORINS
Pharmacodynamics:

Inhibit cell

wall synthesis by binding to the bacterial enzymes (PBPs).

CEPHALOSPORINS
Pharmacotherapeutics:

First-generation

- act primarily against grampositive organisms and used as an alternative to penicillin. Second-generation - act primarily against gramnegative bacteria.

CEPHALOSPORINS
Pharmacotherapeutics

(cont.): Third-generation - act primarily against gramnegative organisms and are the drug of choice for anaerobic organisms. Fourth-generation - active against a wide range of gram-positive and negative bacteria.

( 1st generation) Cefalexin

( 1st generation) Cefadroxil

( 1st generation) Cefradine

(2nd generation) Cefaclor

(2nd generation) Cefuroxime

(3rd generation) Cefotaxime

(3rd generation) Cefixime

(3rd generation) Ceftazidime

(3rd generation) Ceftriaxone

(3rd generation) Ceftizoxime

 Write

the chemical structure of the following: Clavulonic acid Cloxacillin Procaine penicillin (salt)

CEPHALOSPORINS
The

presence of the sex-member ring dihydrothiazine instead of the five-member thiazolidene ring in Penicillin will mean that the -lactam ring is under less stress so it will be less susceptible to act as a substrate for PBP. However the3,4 double bond coupled with a good leaving group at the 3-position will provide the driving force for the reaction.

Presence of 6-member ring

Driving force for the reaction

Structure Activity Relationship Change in R2

Structure Activity Relationship

Changes in R-2 will affect the pharmacokinetic properties of the drug: 1-Methyl 5-thio tetrazole (MTT) group leads to an extended spectrum, higher potency and a longer half-life. It does however come with a price, a serious side effect, as it may cause bleeding due to hypoprothrombonemia.

Structure Activity Relationship

It

will inhibit certain vitamin K-based enzymes that produce various clotting factors and can be reversed by using Vitamin K. Patients at risk for this side effect should be monitored. These compounds also inhibit aldehyde dehydrogenase, causing alcohol intolerance.

1 Methyl, 5-thio tetrazole Change in R2