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Penicillins
Penicillins are beta-lactam antibiotics that were discovered in 1928 by Alexander Fleming. They work by inhibiting the final step of peptidoglycan synthesis in bacterial cell walls. There are several classes of penicillins including natural penicillins, anti-staphylococcal penicillins, and extended spectrum penicillins. They are generally well-absorbed, have varying spectra of activity, and can cause allergic reactions ranging from mild rashes to anaphylaxis. Common adverse effects include hypersensitivity reactions, neutropenia, seizures, and pseudomembranous colitis.
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Penicillins
- 1. PENICILLINS G Vijay NarasimhaKumar Asst. Professor, Dept.of. Pharmacology Sri Padmavathi School of Pharmacy
- 2. •Alexander Fleming wasa 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 andChain received a Nobel prize in 1945 .
- 6. BETA LACTAM ANTIBIOTICS •Theyare selected due to : 1. less adverse effects 2. More safe 3. Non- teratogenic Because they target cell wall
- 7. The Penicillin's consistsof 2 basic structures: 1. Thiazolidine Ring 2. Beta-Lactam Ring
- 8. CELL WALL SYNTHESIS •IN cytoplasm SYNTHESIS OF MUREIN MONOMERS • IN outer surface of cytoplasmic membrane POLYMERISATION • Within cell wall between the layers CROSS LINKING
- 9. SYNTHESISOFMUREINMONOMERS- INCYTOPLASM • 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 pp NAM p NAM CYTOPLASM
- 10. POLYMERIZATIONANDCROSSLINKINGINGRAM POSITIVE --NAG----- --NAG --NAG----------NAG TRANSPEPTIDASES PGT UDP-- -NAG UDP-- -- ----NAG -------- ---NAG CELL MEMBRANE NAM p NAM NAM NAMNAM NAM BETA LACTAM ANTIBIOTICS NAM PERIPLASMIC SPACE
- 11. POLYMERISATIONANDCROSSLINKINGINGRAM 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
- 12. TRANSPEPTIDATION GLYCINE ly G A lyG A ly G A ly G A GLYSINE- ALANINE
- 13.
- 14. MECHANISM OF ACTION NAM NH—CH—C—NH—CH--COOH CH3 O D-ALANINE & D-ALANINE TRANSPEPTIDASE
- 15. 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
- 16. STRUCTURE OF BACTERIALCELL WALL
- 17. peptidoglycan periplasmic space THEGRAM 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
- 18. GRAM -VE PERIPLASMIC SPACE BETA LACTAMASES TRANSPEPTIDASES OUTERLIPID 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
- 19. ACTION OF BETA-LACTAMASEON PENICILLINS INACTIVE PENICILLIN
- 20. CHEMISTRY OF PENICILLINS Responsiblefor 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
- 21. CLASSIFICATIONOFPENICILLINS E.g.: penicillin-G penicillin-V Acts ongram positive – cocci , bacilli and gram negative -cocci Moderate R-group E.g.: Methicillin,Nafcillin, oxacillin, cloxacillin ,dicloxacilin Acts on gram positive – cocci , bacilli Bulky R-group AMOXYCILLIN, AMPICILLIN R- GROUP is small Acts on gram positive and gram negative rods and cocci AMINO PENICILLINS CARBENICILLIN, PIPERACILLIN, TICARCILLIN Small R-Group ANTI- PSEUDOMONAL
- 22. NATURAL PENICILLINS • Thesewill 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 Susceptible to acids but not mostly to beta- lactamases so not used orally Short half life = 10- 20 minutes In salt forms as potassium and Sodium salts Benzathaine and procaine are depot preparations And acts for 3- 4 weeks Not susceptible to acids and used orally Given in salt form as potassium salt
- 23. THERAPEUTICUSES • 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
- 24. ANTI STAPHYLOCOCCALPENICILLINS • Thesehave 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
- 25. EXTENDED SPECTRUM- AMINOPENICILLINS • 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
- 26. INDICATIONS • OTITIS MEDIS– DUE TO STREPTOCOCCUS • SINUSITIS • SKIN AND SOFT TISSUE INFECTIONS • URINARY TRACT INFECTIONS • COMMUNITY ACQUIRED PNEUMONIA • KLEBSIELLA PNEUMONIA • DENTAL ABSCESS • HELICOBACTER PYLORI
- 27. ANTI-PSEUDOMONAL PENICILLINS • CARBENICILLINAND 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
- 28. 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
- 29. CONTD…. • PENICILLINS areHydrophilic 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.
- 30. RESISTANCE NATURAL ACQUIRED HUMANCELLS 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
- 31.
- 32. TYPE-1HYPERSENSITIVITY 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
- 33. TYPE-IIHYPERSENSITIVITY Penicillin changes theantigenicity Of own antigen which leads to Production of antibodies against Own antigen Antibodies against own antigen HEMOLYTIC ANAEMIA
- 34. TYPE–IIIHYPERSENSITIVITY When penicillin's Acts ontissue proteins LIPS-ANGIOEDEMA EYE ORBITALS- PERI ORBITAL EDEMA BLOOD VESSELS- VASCULITIS NEPHRONS-NEPHRITIS PLEURAL CAVITY- PLEURITIS PERICARDIUM-PERICARDITIS
- 35. Contd… PENICILLOIC ACID CHANGES ANTIGENICITY ANTIBODY PRODUCTION ACTSON NEUTROPHILS AND PLATELETS LEADS TO NEUTROPENIA AND THROMBOCYTOPENIA INHIBITS GABA CHANNELS SEIZURES OR CONVULSIONS
- 36. Contd.. • Cationic overloaddue to sodium and potassium ions • Penicillin's destroys normal flora but due to increase in clostridium species EDEMA PSEUDOMEMBRANOUS COLITIS