Penicillins

Introduction to penicillins

1. PENICILLINS G Vijay Narasimha Kumar Asst. Professor, Dept.of . Pharmacology Sri P admavathi S chool of Pharmacy

2. Alexander Fleming was a Scottish biologist and pharmacologist. He was an inventor of penicillin in 1928 . In 1928 Alexander Fleming accidentally discover the antibacterial property of penicillin . Unfortunately the penicillin was unstable and Fleming was unable to purify it Penicillin was finally isolated by Howard Florey and Ernst Chain INTRODUCTION

3. Fleming , Florey and Chain received a Nobel prize in 1945 .

4. BETA LACTAM ANTIBIOTICS They are selected due to : 1. less adverse effects 2. More safe 3. Non- teratogenic Because they target cell wall

5. The Penicillin's consists of 2 basic structures: 1. Thiazolidine Ring 2. Beta-Lactam Ring

6. CELL WALL SYNTHESIS

7. SYNTHESIS OF MUREIN MONOMERS - IN CYTOPLASM UDP-- - NAG – NAG UDP--- UDP- - UDP-- - NAG 2 GLY UDP-- UDP- -- 5 GLY UDP-- ( 5 ) IN GRAM NEGATIVE <----IN GRAM POSITIVE NAG + UDP UDP- -- UDP- -- ENOL PYRUVATE Glucose-6-phosphate TRANSFERASE + amino acids GLUCOSE NAG PEP NADPH NAM L-A GLU L-LY NAM D-A NAM CELL MEMBRANE NAM p p NAM p NAM CYTOPLASM

8. POLYMERIZATION AND CROSS LINKING IN GRAM POSITIVE --NAG----- --NAG --NAG-------- -- NAG TRANSPEPTIDASES PGT UDP-- - NAG UDP-- -- ----NAG -------- ---NAG CELL MEMBRANE NAM p NAM NAM NAM NAM NAM BETA LACTAM ANTIBIOTICS NAM PERIPLASMIC SPACE

9. POLYMERISATION AND CROSSLINKING IN GRAM NEGATIVE CELL MEMBRANE --NAG----- --NAG Peptide linkage --NAG-------- -- NAG TRANSPEPTIDASES PGT UDP-- - NAG ----NAG -------- ---NAG UDP-- CELL MEMBRANE p NAM NAM NAM NAM NAM NAM NAM BETA LACTAM ANTIBIOTICS PERIPLASMIC SPACE

10. TRANSPEPTIDATION GLYCINE ly G A ly G A ly G A ly G A GLYSINE- ALANINE

11. contd..

12. MECHANISM OF ACTION NAM NH—CH—C—NH—CH--COOH CH 3 O D- ALANINE & D-ALANINE TRANSPEPTIDASE

13. continued The ( ) in beta lactam of penicillin's mimics the D-alanine ( ) . The transpeptidase acts on penicillin's rather than alanine And forms an irreversible covalent bond Penicillin's also cause inhibition of Autolysin inhibitors AUTOLYSIN’S helps in cell wall remodelling

14. STRUCTURE OF BACTERIAL CELL WALL

15. peptidoglycan periplasmic space THE GRAM POSITIVE BACTERIA produces large amounts of beta lactamases and are present in cellwall as well as around the cell BETA - LACTAMASES GRAM+VE BETA LACTAMASES

16. GRAM -VE PERIPLASMIC SPACE BETA LACTAMASES TRANSPEPTIDASES OUTER LIPID LAYER CELL CYTOPLASMIC MEMBRANE IN GRAM NEGATIVE BACTERIA the beta lactamases are present in periplasmic space so the penicillin's before acted upon by the trans peptidases will gets inactivated by the Beta lactamases

17. ACTION OF BETA -LACTAMASE ON PENICILLINS INACTIVE PENICILLIN

18. CHEMISTRY OF PENICILLINS Responsible for Bactericidal activity If longer group substitution on R-group then beta lactamase resistant and more lipophilic and has more protein binding ability But If bulky nature It cannot penetrates through Porins of gram negative and tight Peptidoglycans of gram positive NARROW SPECTRUM If smaller R- chain then it acts on both gram positive and gram negative Broad spectrum but gets degraded by acid and beta lactamases

19. CLASSIFICATION OF PENICILLINS PENICILLINS NATURAL/MODERATE SPECTRUM ANTI STAPHYLOCOCCAL OR VERY NARROW SPECTRUM EXTENDED SPECTRUM

20. NATURAL PENICILLINS These will act on the on gram positive – cocci , bacilli and gram negative –cocci as well as miscellaneous which are having peptidoglycan cell wall E.g.: Treponema pallidium PENICILLIN-G PENICILLIN-V

21. THERAPEUTIC USES Actinomycosis Anthrax Clostridium Infections Diphtheria Disseminated gonococcal infections Fuso spirochetosis Haverhill fever Gram negative bacillary bacteremia Endocarditis Meningococcal meningitis Neuro syphillis Rat bite fever Serious streptococcal and staphylococcal infections

22. ANTI STAPHYLOCOCCAL PENICILLINS These have LARGE –R group hence resistant to beta lactamases and is mostly used to treat STAPHYLOCOCCUS INFECTIONS IT has poor penetration due to Bulkier nature and hence NARROW SPECTRUM THEY ARE MOSTLY GIVEN ORALLY Due to IRRATIONAL USE resistance has developed and not used mostly NOW- A- DAYS ADVERSE EFFECTS - METHICILLIN – Interstitial nephritis NAFCILLIN – Nephritis, Neutropenia

23. EXTENDED SPECTRUM - AMINO PENICILLINS AMPICILLIN , AMOXYCILLIN – Hydrophilic AMOXYCILLIN - Easily enters into systemic circulation from Intestine AMPICILLIN – Not well absorbed through intestine and hence used in Intestinal and Genital Infections SMALL R- GROUP hence susceptible to degradation by BETA- LACTAMASES Hence these should be used along with BETA- LACTAMASE INHIBITORS ( CLAVULANIC ACID , SULBACTAM , TAZOBACTUM ) GRAM POSITIVE – COCCI AND BACILLI GRAM NEGATIVE – COCCI , FEW BACILLI H- HEMOPHILUS, H.PYLORI E-ESCHERICHIA COLI L- LISTERIA SPECIES P- PROTEUS S- SALMONELLA TYPHI, SERRATIA

24. INDICATIONS OTITIS MEDIS – DUE TO STREPTOCOCCUS SINUSITIS SKIN AND SOFT TISSUE INFECTIONS URINARY TRACT INFECTIONS COMMUNITY ACQUIRED PNEUMONIA KLEBSIELLA PNEUMONIA DENTAL ABSCESS HELICOBACTER PYLORI

25. ANTI-PSEUDOMONAL PENICILLINS CARBENICILLIN AND PIPERACILLIN ( MOST POTENT) SMALL- R GROUP and hence susceptible to beta- lactamases Hence they should be given along with beta- lactamase inhibitors COMBINATIONS = PIPERACILLIN + SULBACTAM AND PIPERACILLIN + TAZOBACTAM, IV, COSTLY AND used in severe infections such as HEAD INJURY INDICATIONS - Appendicitis , Peritonitis , Septicemia, skin Infections Endometritis , Catheter Related Blood Infections

26. PHARMACOKINETICS ORAL- ANTI- STAPHYLOCOCCAL AMOXYCILLIN, PENICILLIN- V PARENTERAL – PENICILLIN- G, ANTI PSEUDOMONAL PENICILLINS, AMOXYCILLIN DISTRIBUTION- Well Distributed In Extracellular Fluids But DONOT ENTER Intracellular Fluids AS they are HYDROPHILIC they cannot CROSS BLOOD BRAIN BARRIER BUT in case of MENINGITIS THEY CAN CROSS BLOOD BRAIN BARRIER they cross placental barrier. They are not metabolized mostly and hence dose adjustment is not required in hepatic dysfunction

27. CONTD…. PENICILLINS are Hydrophilic and undergoes renal excretion 10% glomerular 90% tubular secretion PROBENICID competes with PENICILLINS for ORGANIC ACID TRANSPORTER and secretes into lumen. This decreases tubular secretion of penicillin and increased penicillin Duration of action.

28. RESISTANCE NATURAL ACQUIRED HUMAN CELLS VIRUSES FUNGI PROTOZOANS DUE TO LACK OF CELLWALL MADE UP OF PEPTIDOGLYCAN ON EXPOSURE TO ANTIBIOTICS - MUTATIONS PLASMIDS CHROMOSOMES If mutations occurs in plasmids they will transfer widely to other species If mutations occurs in chromosomes they will transfers to own species

29. ADVERSE EFFECTS

30. TYPE-1 HYPERSENSITIVITY BOOD VESSELS- VASCULITIS LUNGS- BRONCHOCONSTRICTION SKIN- RASHES GLOMERULAR CAPILLARIES- GLOMERULAR NEPHRITIS PENICILLOIC ACID- when Binds to tissue protein becomes Antigen which is presented to T- Helper cell. LATE REACTION- ANAPHYLAXIS

31. TYPE-II HYPERSENSITIVITY Penicillin changes the antigenicity Of own antigen which leads to Production of antibodies against Own antigen Antibodies against own antigen HEMOLYTIC ANAEMIA

32. TYPE –III HYPERSENSITIVITY When penicillin's Acts on tissue proteins LIPS-ANGIOEDEMA EYE ORBITALS- PERI ORBITAL EDEMA BLOOD VESSELS- VASCULITIS NEPHRONS-NEPHRITIS PLEURAL CAVITY- PLEURITIS PERICARDIUM-PERICARDITIS

33. Contd … PENICILLOIC ACID CHANGES ANTIGENICITY ANTIBODY PRODUCTION ACTS ON NEUTROPHILS AND PLATELETS LEADS TO NEUTROPENIA AND THROMBOCYTOPENIA INHIBITS GABA CHANNELS SEIZURES OR CONVULSIONS

34. Contd.. C ationic overload due to sodium and potassium ions Penicillin's destroys normal flora but due to increase in clostridium species EDEMA PSEUDOMEMBRANOUS COLITIS