Beta lactam antibiotics, PCI syllabus for B.Pharm.

This ppt contains beta lactum antibiotics for B.pharm people. the mechanism of action, classification was well explained. Degradations and generations of penicillins and cephalosporins was covered.

1. MEDICINAL CHEMISTRY III B. Pharmacy III/IV (Second sem.) Dr. K. Purna Nagasree M.Pharm . (BITS, Pilani ), Ph.D., PDF (DST, WOSA) Associate Professor VIGNAN INSTITUTE OF PHARMACEUTICAL TECHNOLOGY (Approved by PCI, AICTE New Delhi and affiliated to JNTUK) ANISO 9001:2015, ISO 14001:2015, OHSAS 18001:2007 Certified institution, beside VSEZ, Duvvada , Vishakapatnam-530049, Andhra Pradesh, India 2021

2. Antibiotics: Historical background, Nomenclature, Stereochemistry, Structure activity relationship, Chemical degradation classification and important products of the following classes . β- Lactam antibiotics: Penicillin, Cepholosporins , β- Lactamase inhibitors, Monobactams Aminoglycosides : Streptomycin, Neomycin, Kanamycin Tetracyclines : Tetracycline , Oxytetracycline , Chlortetracycline, Minocycline, Doxycycline Unit I

3. Sir Alexander Fleming - 1929 , accidentally discovered the antibacterial properties of penicillin Chain and Florey -1939 P enicillin was clinically used - 1941 In 1942, Waksman proposed the search of actinomycetes and discovered streptomycin in 1944. synthetic and semisynthetic agents. Introduction

4. Mechanism of action of β- Lactam antibiotics

5. Penicillins 1. Early penicillins 2. Penicillinase -resistant penicillins 3 . Broad-spectrum penicillins Ampicillin, Amoxycillin Penicillin G, Penicillin V Methicillin, Oxacillins , cloxacillins e tc 4. Anti- pseudomonal penicillins Carbencillin , Ticarcillin

6. Degradation of penicillins

7. Penicillenic acid Penicillin Penicilloic acid Penillic acid Penilloic acid Penamaldic acid Penicillamin+Penaldic acid Penicilloldehyde Acid Alkali

8. The cephalosporins were isolated from the fungus Cephalosporium acremonium in 1948 by Pro Tzu, Newton, and Abraham (1953 ) Cephalosporins contain dihydrometathiazine ring , while penicillin contains a tetrahydrothiazole ( thiazolidine ) ring The cephalosporins are much more acid stable than the corresponding penicillins , . Cephalosporins can be divided into three classes: 1 . Cephalosporin N: penicillin-like structure - a derivative of 6-aminopenicillanic acid. 2 . Cephalosporin P: An acidic antibiotic, which is steroidal in nature . 3 . Cephalosporin-C: It is a true cephalosporin and it is a derivative of 7 amino- cephalosporanic acid – semi synthetic derivatives Cephalosporins

9. Cepham is the name given to the unsubstituted bicyclic lactam . Cephalosporins

10. Orally administered : cephalexin, cephradine , and cefaclor b . Parentrally administered : cephalothin , cephapirin , cephacetrile , and cefazedone . These agents are sensitive to β- lactamase c . Resistant to β- lactamase and parentrally administered : cefuroxime, cefamandole , cefoxitin d . Metabolically unstable : cephalothin and cephapirin Classification Cephalosporins (Route of administration)

11. First generation cephalosporins - Cephalexin, cephadroxil , cephradine and cephalothine Second-generation cephalosporins - Cefaclor , cefamandole Third-generation cephalosporins – Cefotaxime , ceftizoxime Fourth generation – Cefepime , Cefpirome Classification Cephalosporins

12. Degradation of cephalosporins In prescence of strong acids - inactive lactone

13. SAR of cephalosporins 1 . 7-Acylamino substituents: Acylation of amino group generally increases the potency against gram-positive bacteria, but decreases gram-negative potency. Substituents on the aromatic ring that increases lipophilicity provide higher gram- positive activity and generally lower gram-negative activity . The phenyl ring in the side-chain can be replaced with other heterocycles with improved spectrum of activity and pharmacokinetic properties, and these include thiophene , tetrazole , furan, pyridine

14. 2. C-3 substituents: influences pharmacokinetic and pharmacological properties as well as antibacterial activity . Modification at C-3 position has been made to reduce the degradation of cephalosporins . ( i) The benzoyl ester - improved gram-positive activity but lower gram-negative activity. ( ii) Pyridine and imidazole- show improved activity against P. aeruginosa . azide ion with relatively low gram-negative activity . ( iii) aromatic thiols of 3-acetoxy group results in an enhancement of activity against gram-negative bacteria with improved pharmacokinetic properties. ( iv) Replacement of acetoxy group at C-3 position with — CH3, Cl has resulted in orally active compounds. SAR of cephalosporins

15. 3. Introduction of C-7 α- methoxy group shows higher resistance to hydrolysis by β-lactamases 4 . Oxidation of ring sulphur to sulphoxide or sulphone greatly diminishes or destroys the antibacterial activity . 5 . Replacement of sulphur with oxygen leads to oxacepam with increased antibacterial activity , with methylene group - greater chemical stability and a longer half-life . 6 . The carboxyl group of position-4 has been converted into ester prodrugs to increase bioavailability of cephalosporins , and these can be given orally as well. Examples include cefuroxime axetil and cefodoxime proxetil . 7. Olefinic linkage at C 3-4 is essential for antibacterial activity . Isomerization of the double bond to 2-3 position leads to great losses in antibacterial activity SAR of cephalosporins

16. Classes of antibiotics and their spectrum of activity

17. It is more resistant to inactivation by gastric juice than penicillin G and better absorbed from the gastro intestinal (GI) tract. Penicillin V is given to treat ‘trench mouth ’. It is useful in the treatment of streptococcal pharyngitis, pneumonia, arthritis, meningitis , and endocarditis caused by S. pyogenes . Penicillin V

18. It is particularly resistant to inactivation by the penicillinase found in Staphylococci, Bacillus cereus Methicillin sodium has been introduced for use in the treatment of Staphylococci infections caused by the strains resistant to other penicillins . It is given by IM or by slow IV infusion every 4–6 h. Methicillin

19. Use should be restricted to the treatment of infections caused by Staphylococci that are resistant to penicillin G Oxacillins (Phenyl methyl Isoxazolyl penicillins )

20. It is used to treat urinary tract infections and respiratory tract infections The α-amino group plays an important role in the broader activity . A mpicillin stable to acid hydrolysis and instable to alkaline hydrolysis . Pivampicillin is a prodrug of ampicillin Ampicillin

21. It is effective in the treatment of systemic and urinary tract infections. The carboxyl group is thought to provide improved penetration of the molecule through the cell wall barriers of gram-negative bacilli as compared with other penicillins . acid labile being a malonic acid derivative, it decarboxylates readily to penicillin G. It has low toxicity, and interferes with platelet function resulting in bleeding Carbenicillin

22. It is particularly recommended for urinary tract infection The α-amino group of cephalexin renders it acid stable . The 3-methyl group is responsible for the metabolic stability . Cephalexin (phenyl acetamido 7ACA)

23. a second-generation cephalosporin antibiotic with bactericidal activity. Cefamandole is active against Haemophilus and gram-negative bacilli susceptible to other cephalosporins . solutions are stored for 24 h at room temperature or up to 96 h by refrigeration Cefamandole

24. It is a beta lactamase resistant cephalosporin , used in lower respiratory infection and meningitis Cefpirome (4 th generation ) is used to treat susceptible infections, including urinary and respiratory tract infections, skin infections, septicaemia, and infections in immuno -compromised patients. Ceftizoxime sodium 2-(2-amino-1,3-thiazol-4-yl)-2-( methoxyimino )acetyl] 7 ACA  

25. cephalosporins Allergic manifestation : The cephalosporins should be avoided or used with caution in individuals allergic to penicillins . When cefamandole or cefoperazone is ingested with alcohol, a disulphiram like effect is seen ii . Bleeding: Bleeding can occur with cefemandole or ceforperazone because of antivitamin K effects. But the administration of the vitamin overcomes this problem. Adverse reactions

26. Penicillins - Anaphylactic shock Common  allergic  reactions to  penicillin  include rashes etc itchy eyes, and swollen lips, tongue, or face. In rare cases, an allergy to  penicillin  can cause an  anaphylactic reaction (in an hour) which can be deadly Epinephrine Adverse reactions

27. Unlike other beta-lactams, the monobactam contains a nucleus with no fused ring attached. Thus, there is less probability of cross-sensitivity reactions. Example : Aztreonam Mono bactams

28. Although they exhibit negligible antimicrobial activity, they contain the β-lactam ring. prevent the inactivation of β-lactam antibiotics by binding the β-lactamases they are co-administered with β-lactam antibiotics. These drugs are irreversible inhibitors of β-lactamase these bind the enzyme and do not allow it to interact with the antibiotic Beta lactamase inhibitors