ANTIBIOTICS[PENICILLINS] MEDICINAL CHEMISTRY BY RAVISANKAR

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ANTIBIOTICS[PENICILLINS} MEDICIANL CHEMISTRY BY P.RAVISANKAR …

ANTIBIOTICS[PENICILLINS} MEDICIANL CHEMISTRY BY P.RAVISANKAR
VIGNAN PHARMACY COLLEGE
VADLAMUDI
GUNTUR- A.P
INDIA

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  • 1. ANTIBIOTICSWhen antibiotics were first discovered they were called “wonder drugs”AntibacterialsAntibiotic is a drug that fights bacterialinfectionprof. RavisankarVignan Pharmacy collegeValdlamudiGuntur Dist.Andhra PradeshIndia.banuman35@gmail.com00919059994000penicillins
  • 2. ““AntibioticsAntibiotics are defined as chemical substances or compoundsare defined as chemical substances or compoundsproduced by various species of microorganisms such as bacteriaproduced by various species of microorganisms such as bacteriaand fungi ,which in low concentrations destroy, kill) or inhibit theand fungi ,which in low concentrations destroy, kill) or inhibit thegrowth of other species of microorganisms.”growth of other species of microorganisms.”Anti = against ; bios = lifeAnti = against ; bios = lifeAn antibiotic is a chemical substance produced by one organismAn antibiotic is a chemical substance produced by one organismthat is destructive to another.that is destructive to another.The word antibiotic came from the wordThe word antibiotic came from the word antibiosisantibiosis a terma termcoined in 1889 by Louis Pasteurs pupil Paul Vuillemin whichcoined in 1889 by Louis Pasteurs pupil Paul Vuillemin whichmeans a process by which life could be used to destroy life.means a process by which life could be used to destroy life.Over 3,000 antibiotics have been identified but only a few dozenOver 3,000 antibiotics have been identified but only a few dozenare used in medicine.are used in medicine.DEFINITION:
  • 3. Requirements for a substance to be considered as an antibioticRequirements for a substance to be considered as an antibiotic--It should have aIt should have a wide spectrumwide spectrum of activity with the ability to destroy or inhibit many differentof activity with the ability to destroy or inhibit many differentspecies of pathogenic organisms.species of pathogenic organisms. -It should be-It should be eliminated completelyeliminated completely from the body.from the body. -It should-It should not produce adverse and side effectsnot produce adverse and side effects.. -It should inhibit or-It should inhibit or abolishabolish the growth of micro- organisms.the growth of micro- organisms. - It should be- It should be highly effectivehighly effective in low concentrations.in low concentrations. -It should be-It should be nonallergenicnonallergenic to the host.to the host. -It should-It should notnot eliminate theeliminate the normal floranormal flora of the host.of the host. -It should be-It should be able to reachable to reach the part of the human body wherethe part of the human body wherethe infection is occurring.the infection is occurring. -It should be-It should be inexpensiveinexpensive andand easy to produceeasy to produce.. -It should be-It should be chemically-stablechemically-stable (have a long shelf-life).(have a long shelf-life).
  • 4.  HHistory of antibiotics can be described inistory of antibiotics can be described in two segmentstwo segments early history and modernearly history and modernhistoryhistory.. Most important is the discovery of penicillin by SIRMost important is the discovery of penicillin by SIR Alexander Fleming.Alexander Fleming. EARLY HISTORYEARLY HISTORY:: During ancient timesDuring ancient times :: Long ago before 20Long ago before 20ththcentury there was no proper treatment for diseases.century there was no proper treatment for diseases.The diseases caused by Mycobacterium tuberculosis, Mycobacterium leprae were not identified.The diseases caused by Mycobacterium tuberculosis, Mycobacterium leprae were not identified. Over 2,500 years ago , Chinese used plants and moulds to treat infected wounds.Over 2,500 years ago , Chinese used plants and moulds to treat infected wounds. The ancientThe ancient Egyptians used honey+lint(softEgyptians used honey+lint(soft cotton cloth covering and protecting wounds)cotton cloth covering and protecting wounds)++lardlard(melted fat of pigs) used as ointment for dressing wounds.(melted fat of pigs) used as ointment for dressing wounds. Egyptians have often been found onions in body cavities of mummies. They used onions,Egyptians have often been found onions in body cavities of mummies. They used onions,garlic and radish herb also been used therapeutically. Infact they have anti-infective properties.garlic and radish herb also been used therapeutically. Infact they have anti-infective properties. GreeksGreeks and Indians usedand Indians used mouldsmoulds and other plants to treat infections.and other plants to treat infections. InIn Greece and Serbia, moldy breadGreece and Serbia, moldy bread was traditionally used to treat wounds andwas traditionally used to treat wounds andinfections.infections. Warm soilWarm soil was used inwas used in RussiansRussians to cure infected wounds.to cure infected wounds. Sumerian doctorsSumerian doctors gave patientsgave patients beer soup mixed with turtle shells and snakebeer soup mixed with turtle shells and snakeskinsskins.. Babylonian doctorsBabylonian doctors healed the eyes using a mixture ofhealed the eyes using a mixture of frog bile and sour milkfrog bile and sour milk ..-Sri Lankan army-Sri Lankan army usedused oil cake (sweetmeat)oil cake (sweetmeat) to serve as antibacterial.to serve as antibacterial.
  • 5. Treatment of Infectious Diseases prior to Antibiotics
  • 6. Modern HistoryModern History Late 1800’s = Search for antibiotics began with the growing acceptance of the germ theoryLate 1800’s = Search for antibiotics began with the growing acceptance of the germ theoryof disease(of disease(Louis Pasteur was one of the first recognized physicians who observed that bacteriaLouis Pasteur was one of the first recognized physicians who observed that bacteriacould be used to kill other bacteria)could be used to kill other bacteria) 1871 = The surgeon joseph lister found urine contaminated with1871 = The surgeon joseph lister found urine contaminated withmould couldnt kill the bacteria.mould couldnt kill the bacteria. 1890’s = German doctors Rudolf emmerich,oscar low made1890’s = German doctors Rudolf emmerich,oscar low madepyocyansepyocyanse from microbes. It was the first antibiotic usedfrom microbes. It was the first antibiotic usedin hospitals but the drug did not work.in hospitals but the drug did not work. 1909 =First modern chemotherapeutic agent1909 =First modern chemotherapeutic agent SALVARSANSALVARSAN for thefor thetreatment of syphilis.(paul Ehrlich)treatment of syphilis.(paul Ehrlich) 19281928 = Scottish bacteriologist= Scottish bacteriologist Sir Alexander Fleming discovered enzymeSir Alexander Fleming discovered enzymelysozyme and the antibiotic substance penicillin.lysozyme and the antibiotic substance penicillin. 1932 = Gerhard Domagk discovered1932 = Gerhard Domagk discovered ProntosilProntosil a prodrug.a prodrug. 1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.1936 = Sulfanilamide the first synthetic sulfonamide in human medicine. 1940 =1940 = Invention of Modern Drug Discovery: Ehrlich & The Magic Bullet meansCompound that selectively targets a disease causingorganism while havingnonegative effect on human tissuenonegative effect on human tissue .. 1940 =First therapeutic use of penicillin by Floury.1940 =First therapeutic use of penicillin by Floury. 1944 = Selman waksman made Streptomycin from soil bacteria.1944 = Selman waksman made Streptomycin from soil bacteria. 1948 = Chlortetracycline.1948 = Chlortetracycline. 1957 = Nystatin (fungal infections)1957 = Nystatin (fungal infections) 1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin) 1980 =Norfloxacin, the first fluoroquinolone.1980 =Norfloxacin, the first fluoroquinolone. 1980 =Enroflocacin.1980 =Enroflocacin. 1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tabletsthe first sold antibiotic under the trade names of Amoxil and trimox.the first sold antibiotic under the trade names of Amoxil and trimox.
  • 7.  CLASSIFICATIONCLASSIFICATION :: Antibiotics are classified in many ways based on chemical structure, its spectrum ofAntibiotics are classified in many ways based on chemical structure, its spectrum ofactivity, source, and pharmacological activity.activity, source, and pharmacological activity. Based on the chemical structureBased on the chemical structure :: 1.1.β-lactam antibioticsβ-lactam antibiotics : Penicillins, Cephalosporins,carbapenems,monobactams.: Penicillins, Cephalosporins,carbapenems,monobactams. 2.2. Amino glycoside antibioticsAmino glycoside antibiotics : Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin,: Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin,Amikacin.Amikacin. 3.3. TetracyclinesTetracyclines:: Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline.Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline.methacycline,meclocycline.methacycline,meclocycline. 4.4. Macrolide antibioticsMacrolide antibiotics : Erythromycin, Clarithromycin, Azithromycin.: Erythromycin, Clarithromycin, Azithromycin. 55.. PolypeptidePolypeptide antibioticsantibiotics : Vancomycin, Bacitracin, Polymyxin B, Nystatin, Gramicidin.: Vancomycin, Bacitracin, Polymyxin B, Nystatin, Gramicidin. 6.6.QuinolonesQuinolones :Ciprofloxacin.:Ciprofloxacin. 7.Sulfa antibiotics7.Sulfa antibiotics : Sulf isoxazole.: Sulf isoxazole. 8.8. MiscellaneousMiscellaneous: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid.: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid. Based on the sourceBased on the source:: They are divided in to three typesThey are divided in to three types.. Natural antibioticsNatural antibiotics : Penicillium chrysogenum-----Penicillin.: Penicillium chrysogenum-----Penicillin. Bacillus subtilis ---------------- Bacitracin.Bacillus subtilis ---------------- Bacitracin. Bacillus polymyxa------------- Polymixin.Bacillus polymyxa------------- Polymixin. Stryptomyces griseus---------- Stryptomycin.Stryptomyces griseus---------- Stryptomycin. Streptomyces venezulae------- Chloramphenicol.Streptomyces venezulae------- Chloramphenicol. Synthetic antibioticsSynthetic antibiotics :: These are synthetically prepared on commercial basis.These are synthetically prepared on commercial basis. Chloramphenicol palmitate, alpha aminobenzyl penicillin.Chloramphenicol palmitate, alpha aminobenzyl penicillin. Semisynthetic antibioticsSemisynthetic antibiotics : These antibiotics are commercially synthesized by adding chemical: These antibiotics are commercially synthesized by adding chemicalcompounds, amides etc., to the natural antibiotics.In these the main part of the chemical structure iscompounds, amides etc., to the natural antibiotics.In these the main part of the chemical structure isobtained from the micro-organisms which are then modified by adding various chemical moieties as the sideobtained from the micro-organisms which are then modified by adding various chemical moieties as the sidechain.chain. Ex: Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin.Methicillin.Ex: Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin.Methicillin. BiosyntheticBiosynthetic : :Benzylpenicillin, Phenoxymethylpenicillin.: :Benzylpenicillin, Phenoxymethylpenicillin. Spectrum ActivitySpectrum Activity :: Broad spectrumBroad spectrum: These antibiotics inhibit the growth of wide range (i.e. More than one species) of: These antibiotics inhibit the growth of wide range (i.e. More than one species) ofmicroorganisms.Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria.microorganisms.Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria. EX: Cephalosporins, Chloramphenicol, Tetracycline’s.EX: Cephalosporins, Chloramphenicol, Tetracycline’s. Narrow spectrumNarrow spectrum: These antibiotics are effective mainly against Gram +ve (or) Gram –ve bacteria.: These antibiotics are effective mainly against Gram +ve (or) Gram –ve bacteria.
  • 8. 1928Alexander Fleming (1881-1955)Penicillin was discovered by chance in 1928Fleming noted a fungus growing on his bacterial plateshad killed off the surrounding bacteria
  • 9. Penicillium mould(penicillium notatum)
  • 10. In 1929 Alexander Fleming discoveredthe compound produced by the fungus.The fungus was called Penicillium notatumThe isolated compound he called PenicillinThis newly discovered active substance penicillin was. effective even when diluted up to 800 times.
  • 11. Inhibition of bacterialgrowth around thepenicillium mould.Different species of penicillium
  • 12. Historical background of penicillinsHistorical background of penicillins Alexander Fleming was born in Loudon, Scotland on 6 August, 1881 in aAlexander Fleming was born in Loudon, Scotland on 6 August, 1881 in afarming family.farming family. He carried on his schooling atHe carried on his schooling at Regent StreetRegent Street PolytechnicPolytechnic after his familyafter his familymoved to London in 1895.moved to London in 1895. He joinedHe joined St. Marys Medical SchoolSt. Marys Medical School and became research assistant toand became research assistant torenowned Sir Almroth Wright after he qualified withrenowned Sir Almroth Wright after he qualified with distinctiondistinction in 1906.in 1906. He completed his degreeHe completed his degree (M.B.B.S.)(M.B.B.S.) withwith gold medalgold medal in 1908 from thein 1908 from theUniversity of London and lectured at St. Mart till 1914.University of London and lectured at St. Mart till 1914. He served asHe served as CaptainCaptain during theduring the World War IWorld War I and worked in battlefieldand worked in battlefieldhospitals in France.hospitals in France. After the war he returned to St. Mary in 1918 and got electedAfter the war he returned to St. Mary in 1918 and got elected Professor ofProfessor ofBacteriology in 1928.Bacteriology in 1928. He discovered naturally antiseptic enzyme in 1921, which he namedHe discovered naturally antiseptic enzyme in 1921, which he namedlysozymelysozyme. This substance existed in tissues and secretions like mucus,. This substance existed in tissues and secretions like mucus,tears and egg-white but it did not have much effect on the strongly harmfultears and egg-white but it did not have much effect on the strongly harmfulbacteria.bacteria. It was in 1928 when he observed while experimenting onIt was in 1928 when he observed while experimenting on influenza virusinfluenza virusthat a common fungusthat a common fungus..
  • 13.  The date of his breakthrough was on the morning of Friday, September 28, 1928.The date of his breakthrough was on the morning of Friday, September 28, 1928.It was aIt was a Serendipitous observation(fortuitous accident)Serendipitous observation(fortuitous accident) i.e (happening by chance) ini.e (happening by chance) inhis laboratory in the basement of St. Marys Hospital in london( now part of impericalhis laboratory in the basement of St. Marys Hospital in london( now part of impericalcollege.college. As the story goes, one day in 1928 Fleming left the lid off theAs the story goes, one day in 1928 Fleming left the lid off thetop of one of his Petri dishes for a little too long, and a fungaltop of one of his Petri dishes for a little too long, and a fungalspore landed on it (the culture became contaminated). Afterspore landed on it (the culture became contaminated). Afterreturning from vacation, Fleming noticed that hisreturning from vacation, Fleming noticed that hisStaphylococcusStaphylococcus culture was contaminated with this fungus - butculture was contaminated with this fungus - but- instead of throwing the Petri dish away, he- instead of throwing the Petri dish away, he carefullycarefullyexamined it first.examined it first. There was a inhibited bacterial growth around the mould. Fleming concluded thatThere was a inhibited bacterial growth around the mould. Fleming concluded thatthe mould(fungal colony) was releasing a antibacterial substance which wasthe mould(fungal colony) was releasing a antibacterial substance which wasspreading into the surrounding area where the bactrial colonies were dying.i.e. lysingspreading into the surrounding area where the bactrial colonies were dying.i.e. lysingthe bacteriathe bacteria.. One more important event was the weather conditions were also ideal at that time.One more important event was the weather conditions were also ideal at that time. He grew a pure culture and discovered that it was aHe grew a pure culture and discovered that it was a PenicilliumPenicillium mould, nowmould, nowknown to beknown to be Penicillium notatum.Penicillium notatum. Penicillium mould must secrete an antibacterial substance, and the first to isolatePenicillium mould must secrete an antibacterial substance, and the first to isolatecrude active substance which he named penicillin.crude active substance which he named penicillin.
  • 14.  This newly discovered active substance(penicillin) wasThis newly discovered active substance(penicillin) waseffective even when diluted up toeffective even when diluted up to 800800 times.times. Unfortunately,the substance was alsoUnfortunately,the substance was also unstable andunstable andFleming was unableFleming was unable to purify the compoundto purify the compound . He. Hetherefore came to the conclusion that penicillin was tootherefore came to the conclusion that penicillin was toounstable to be used clinically.unstable to be used clinically. Florey and ChainFlorey and Chain by using processes such asby using processes such as freeze-freeze-drying and chromatographydrying and chromatography which allowed isolation ofwhich allowed isolation ofthe penicillinthe penicillin.. Fleming, Florey, and Chain shared theFleming, Florey, and Chain shared the 1945 Nobel Prize1945 Nobel Prizefor medicine for their work on penicillinfor medicine for their work on penicillin.. In june 1942 availability of penicillin was just to treat 10In june 1942 availability of penicillin was just to treat 10patients.patients. After fermentation research 2.3 million doses had beenAfter fermentation research 2.3 million doses had beenincreased in U.S.increased in U.S.
  • 15. Fleming, Florey, and Chain shared the 1945 Nobel Prize forFleming, Florey, and Chain shared the 1945 Nobel Prize formedicine for their work on penicillinmedicine for their work on penicillin..1938, Problem of isolating penicillin solved by Florey and Chain using a process called"freeze drying" now called lyophilization
  • 16. Natural Penicillin was toounstable a compoundIt could not be producedin significant quantities
  • 17. Oxford scientists sent the data to the USA1943 the mass production of penicillin began
  • 18.  Once the penicillin is released from the fungal cells, the compoundOnce the penicillin is released from the fungal cells, the compoundis isolated from the fermenters contents and purified by specialis isolated from the fermenters contents and purified by specialbiochemical processes.biochemical processes. Such commercial production results in more than 100,000,000Such commercial production results in more than 100,000,000pounds of penicillin production per yearpounds of penicillin production per year
  • 19. Biological sources of penicillinBiological sources of penicillin The first naturally occurring benzyl penicillin (penicillin G) was obtained byThe first naturally occurring benzyl penicillin (penicillin G) was obtained bythe fermentation of fungusthe fermentation of fungus Penicillium notatumPenicillium notatum .. At present it is obtained from a highly yielding strain calledAt present it is obtained from a highly yielding strain called PenicilliumPenicilliumchrysogenumchrysogenum .. 30 different biosynthetic penicillins have been isolated from various strains30 different biosynthetic penicillins have been isolated from various strainsofof Penicillium notatiumPenicillium notatium andandPenicillum chrysogenum.Penicillum chrysogenum.
  • 20. ONSNHCOOHCH3CH3COPenicillin GHas undergone a number of chemical modifications.PenicillinG is self destructive mechanism built in its structure.Because of influence of Acyl side chain i.e. neighbouring groupparticipation.Penicillin G is not acid stable. It is given by parenteral route.Structures of different penicillins:(Benzyl penicillin)
  • 21. ONSNHCOOHCH3CH3COOPenicillin VPhenoxy methyl penicillin•By placing electron with drawing group in the side chain which could draw electronsaway from the corbonyl oxygen and reduce its tendency to act as a nucleophile.•Penicillin-v has electro –ve oxygen on the acyl side chain with electron withdrawingeffect.•This is more acid stability than penicillinG•It is more stable in acid in the stomach, so it can be given orally.•Infact acid sensitivity can be solved by having an electron withdrawing group on theAcyl side chain.It withdraws theelectrons awayfromthe corbonyloxygen and reducethe tendencyto act as anucleophile.
  • 22. ONSNHCOOHCH3CH3CO0CH30CH3Methicillin“steric shields” can be added to penicillins to protect them from bacterialBetalactamase(peicillinase) enzymes.By placing bulky groups on the side chain it prevent the penicillin from entering the penicillinaseor beta lactamase active site.Infact steric shield should not be too bulkey. If it is too bulkey it also Prevents the penicillin fromattacking the transpeptidase target enzyme.It should not be too small enough.. Methicillin is also not a idal drug. Infact methicillin hasno electron withdrawing group on the side chain. It is acid sensitive and has to be injected.Steric shieldsare the two0-methoxygroups on thearomatic ringInfact no electron withdrawingGroup is present on the side chainIt is acid sensitive, and has tobe injected.Bulky group
  • 23. ONSNHCOOHCH3CH3COIsoxazolyl PenicillinsONCH3R1R2R1 R2Oxacillin H HCloxacillin Cl HDicloxacillin Cl ClBetter penicillinase resistant agents have beendeveloped.The isoxazolyl ring acts as the steric shield butIt is also electron-withdrawing giving theStructure acid stability.Flucloxacillin Cl F
  • 24. ONSNHCOOHCH3CH3CONH2AmpicillinSpecturm of activity shown by any penicillin depends on its structure., ability to cross the cell membrane of gram-ve bacteriaIts susceptibility to betalactamasesIts affinity for transpeptidase target enzyme.Hydrophobic groups on the side chain( Ex: penicillin G) favour activity against Gram-positive bacteriaHydrophilic groups on the side chain have increase in activity against Gram –negative bacteria.If the hydrophilic group is (NH2,OH,CooH group) attached to the carbon, alpha to the carbonyl group on the side chain.All have an alpha hydrophilic group which aids the passage of these penicillins through the porins of the Gram-veBacterial outer cell membrane.The acidic stability of theampicillin is alsoAttributed the electronwithdrawing character of theprimary aminogroup whichprevents the hydrolysis of thebetalactumbond.It is susceptable toDegradation by betalactamaseenzymes.Hence it is given byCombination withBetalactamase inhibitors likesulbactum,gentamycin.
  • 25. ONSNHCOOHCH3CH3CONH2OHAmoxicillinAmoxycillin is the very similar in structure like ampicillin, the only difference beingAn extra phenol group on amoxycillin.*similar spectrum of activity to penicillinG, but more active against Gram-ve bacteria*Acid resistant due to the –NH2 group and therefore orally active.*Non toxic*Sensitive to beta lactamase(No shield)---Can cause diarrhoea due to poor absorption through the gut wall, is due to dipolar nature of the moleculeIt has both free carboxylic acid and amino function. This problem can be solved by using a prodrugPivampicillin,talampicillin,bacampicillin are prodrugs of ampicillin.acyloxymethyl esters are used to mask the-cooH groups. Its spectram of activity is increased when administered with clavalunic acid.Broad spectrum activityIs associated with thePresence of anAlpha hydrophilic groupOn the acyylSide chain of penicillin.Here extra phenol groupOn amoxycillin if youCompare with ampicillin.It is better absorbedThrough gut wall.Uses:BronchitisPneumoniaTyphoidEnteric feverGonorrhoeaUrinary tractinfactions.
  • 26. 5 Classes of PenicillinsNatural PenicillinsPenicillin G / Penicillin VPenicillinase Resistant PenicillinsMethicillinNafcillinIsoxazoly Penicillins (Cloxacillin / Dicloxacillin / Oxacillin / Flucloxacillin)AminopenicillinsAmpicillin / AmoxicillinCarboxypenicillinsTicarcillinUreidopenicillinsPiperacillin / Mezlocillin / AzlocillinCanadian Formulary Penicillins
  • 27. Structures of different penicillins
  • 28. Nomenclature of penicillisnsNomenclature of penicillisnsNomenclature of penicillins is done to different systems.Nomenclature of penicillins is done to different systems.Chemical abstract system(CAS):•According to this system penicillins are numbered starting from “S” atom.•Sulpher atom is assigned the 1stposition and “N” atom is assigned number 4.1234567Bicyclic ring system6-acylamino-2,2-dimethyl-3-corboxylic acid.United states Pharmacopoeia (USP system):•The usp system of naming penicillins is the reverse of CA system•According to this system the nitrogen atom is given the 1stposition and “S” atomis assigned the 4thpostion.1 2345674-thia-1-azabicyclo 3.2.0 Heptane.1 22345671 234567
  • 29. 3.As derivatives of Penam:Unsubstituted bicyclic system together withcorbonyl group has been named as penam.According to this method penicillins are named as ……….4. As derivatives of penicillanic acid:In this method penicillins are named as derivatives of penicillanic acid ring systemwith 2,2-dimethyl and corboxyl groups as substituents at position 2 and 3 respectly.Penicillanic acid1 235. As derivatives of penicillins (on the basis of “R” group) … TRIVAL SYSTEMIn this system 6-corbonyl amino penicllanic acid portion of the molecule is namedAs penicillin and the different penicillins are distinguished on the basis of “R” groupon the acyl amino side chain.234567
  • 30. 6- corbonyl amino penicllanic acidPortion of the molecule is named as penicillin.R= benzyl group ( C6H5-CH2)R= Phenoxy methyl group ( named as phenoxymethyl-Penicillin) or Penicillinv.This system of naming of penicillins is simple and serves as a goodMeasure for naming and comparing closely related penicillin structures.
  • 31. Reactions:Hydrolysis of penicillins by hot and cold dilute mineral acidReactions:Hydrolysis of penicillins by hot and cold dilute mineral acid
  • 32.  EarEarly commercial penicillinly commercial penicillinYellow to brown amorphous powderSo unstable that refrigeration is required to maintain activity even forShort timeCrystalline penicillins are when kept dry are stable for years with outrefrigeration..•Cold conditions retain stability.•Hydroalcoholic solutions of penicillins are as stable as aqeoussolutions.Reason: Penicillins are inactivated by metal ions such as Zn and Cu.•Oxidising agents also inacivate penicillins.•Temperature affects the rate of deterioration.so by controlling the PH
  • 33.  PenicillinG sodium or potacium should bePenicillinG sodium or potacium should beprotected from moisture to prevent hydrolysisprotected from moisture to prevent hydrolysisof the compound.of the compound.penicillin tabltes or power for oral solutionspenicillin tabltes or power for oral solutionsshould be stored at room temparature in tightshould be stored at room temparature in tightcontainers to avoid exposure of excessivecontainers to avoid exposure of excessiveheat.heat.Oral powder for solutions should be stored for 2-Oral powder for solutions should be stored for 2-8800cc((refrigerated) and discarded after 14days.refrigerated) and discarded after 14days.PenicillinG procaine 2-8PenicillinG procaine 2-8ooccAfter reconstituting the injectable solution isAfter reconstituting the injectable solution isstable for 7days.stable for 7days.
  • 34. Most reactive carbonyl essential for activity.Variable groupBicyclic system essentialSite of penicillinase action(break in beta lactum ring(that bond is broken by betalactamase or penicillinaseEnzyme.(the bond b/n c and N is broken by β-lactamase (or)penicillinase enzme.D-valinecystineBicyclic system is essential6-amino penicillanic acid(6-APA)This portion is commonFor all types of penicillinsThe “R”groupdetermines theStability andImproved spectrumof activity andPharmacokineticadvantages.Cis stereochemistry is essentialfree corboxylateIs essentialBasic chemistry: Betalactum ring + Thiazolidine ring.---L-
  • 35.  Key features of structure 1. β-lactam ring a. "Lactam" is a word for any cyclic amide (the word "lactone" is used for a cyclicester) b. a β-lactam means that the nitrogen is joined to the carbon which is beta to thecarbonyl c. this creates strain in the ring, since it is a four membered ring d. b-lactam becomes good acylating agent for active site serine of penicillinbinding protein 2. Carboxylate a. Negatively charged at neutral pH b. Anchors drug in active site pocket (positively charged) 3. Acylamido side chain a. Necessary for biological potency b. Proper stereochemistry of attachment to ring essential for activity c. Variation at side chain can dramatically affect biological activity againstvarious strains of bacteria D. Common Early Penicillins 1. Penicillin G had to be administered parenterally, since it is not acid stable 2. Penicillin V has more acid stability, and can be administered orally
  • 36. Penicillins are….a group of antibiotics that contain 6-amino penicillanic acid side chain attachedto the 6-amino group.•The penicillin nucleus is the chief structural requirement for biological activity.•The side chain structure determines the many of the antibacterial andpharmacological characterstics.•The strained β-lactum ring is essential.•Penicillin contains β-lactum ring is fused with thiazolidine ring.•The free carboxylic acid is essential. The carbolated ion is binds to the chargedammonium ion of lysine residue in the binding site.•The bicyclic system is important. The greater the strain, the greater the activity.•The acyl amino side chain is essential.•Sulfur is usual but not essential.•The cis- stereo chemistry of bicyclic ring with respect to the acyl amino side chain isimportant.•Oxidation of sulphur to a sulfone or sulfoxide will decrease the activity.•The methyl groups at position 2 are essential.•β- lactum corbonyl group at position “7” is must.•The carboxylic acid is changed to an alcohol or ester activity is decreased.•“N” at position 4 is must for antibacterial activity.•Penicillin molecule contains a ‘3’ chiral carbon atome c-3,c-5,c-6. Disruption of•These spacial arrangements results in loss of activity.
  • 37.  SAR of “R”group:SAR of “R”group: C-6 amino west end substitution:C-6 amino west end substitution:The design and development of the west-end substituents hasThe design and development of the west-end substituents hasbeen aimed at strenghthing of activity,stability,resistance, absorption and distribution.been aimed at strenghthing of activity,stability,resistance, absorption and distribution. Placing the electron withdrawing group in the side chainPlacing the electron withdrawing group in the side chainwhich could draw electrons away from the carbonyl oxygen and reduce the tendencywhich could draw electrons away from the carbonyl oxygen and reduce the tendencyto act as a nucleophine and allows a greater stability and oral availability. Ex:to act as a nucleophine and allows a greater stability and oral availability. Ex:penicillin V,ampicillin.penicillin V,ampicillin. Steric shields can be added to penicillin to protect them from bacterial betalactamaseSteric shields can be added to penicillin to protect them from bacterial betalactamaseenzymes.enzymes. By placing bulky groups on the side chain it prevent the penicillin from entering theBy placing bulky groups on the side chain it prevent the penicillin from entering thepenicillinase or betalactamase active site.penicillinase or betalactamase active site. Infact if the steric shield was too bulkey then it also prevents the penicillin fromInfact if the steric shield was too bulkey then it also prevents the penicillin fromattacking the transpeptidase target enzyme, It should be ideal sheld.attacking the transpeptidase target enzyme, It should be ideal sheld.but it should not be too small enough…but it should not be too small enough…Ex: Methicillin. Indeed methicillin has no electron with drawing group on the sideEx: Methicillin. Indeed methicillin has no electron with drawing group on the sidechain. It is acid sensitive and has tobe injected.chain. It is acid sensitive and has tobe injected. Incorporation of isoxazolyl ring in to the penicillin side chain lead toIncorporation of isoxazolyl ring in to the penicillin side chain lead tothe better penicillinase resistant agents have been developed.the better penicillinase resistant agents have been developed.Infact isoxazolyl ring acts as the steric shield but also electron withdrawing groupInfact isoxazolyl ring acts as the steric shield but also electron withdrawing groupgiving the structure acid stability.giving the structure acid stability.
  • 38.  Ex:oxacillin,cloxacillin,dicloxacillin,Flucloxacillin.Ex:oxacillin,cloxacillin,dicloxacillin,Flucloxacillin. Broad spectrum activity is associated with the presence ofBroad spectrum activity is associated with the presence ofαα-hdrophillic group on the acyl side chain of penicillin.-hdrophillic group on the acyl side chain of penicillin. Enhancement of GramEnhancement of Gram ––ve activity is increased hydrophilic groupve activity is increased hydrophilic group(-NH2,OH,-CooH group), attached to the Carbon,(-NH2,OH,-CooH group), attached to the Carbon,αα to the carbonyl group onto the carbonyl group onthe side chain.the side chain.these penicillins are having useful activity against both remove and gram-Vetthese penicillins are having useful activity against both remove and gram-Vetbacteria are known as broad spectrum antibiotics.bacteria are known as broad spectrum antibiotics.EX: Ampicillin and Amoxicillin.EX: Ampicillin and Amoxicillin. The spectrum of activity was further extended with introducing strong acidicThe spectrum of activity was further extended with introducing strong acidicgroup is attached to the carbongroup is attached to the carbon αα- to the carbonyl group on the side chain.- to the carbonyl group on the side chain.αα-corboxy penicillins are broad spectrum penicillins and wider range of-corboxy penicillins are broad spectrum penicillins and wider range ofgram-ve activity than ampicillin.gram-ve activity than ampicillin.EX: Carbencillin,Ticarcillin.EX: Carbencillin,Ticarcillin. The acylation of the ampicillin west-end amine functionality withThe acylation of the ampicillin west-end amine functionality withcertain polar groups leads to cyclic urea derivatives.certain polar groups leads to cyclic urea derivatives.Ureido penicillins have a urea functional group atUreido penicillins have a urea functional group at αα-position.Infact they are-position.Infact they aremore active than the carboxypenicillins against streptococci and Haemophilusmore active than the carboxypenicillins against streptococci and Haemophilusspecies. Presence of urea group gives improved penetration in to gram-vespecies. Presence of urea group gives improved penetration in to gram-vespecies.species.EX; Azocillin,Mezlocillin,Piperacillin.EX; Azocillin,Mezlocillin,Piperacillin.
  • 39. Penams are a subclass of the broader β-lactam family of antibiotics and relatedcompounds. Penams contain a β-lactam ring fused to a 5-membered ring, where one ofthe atoms in the ring is a sulfur and the ring is fully saturated. Penicillin is a member ofthis family of compoundsThe β-lactum ring --- i.e the four membered ring makes the molecule thermodynamically unstable.This is easily hydrolysed by acids.The penicillin derived from the naturalSource need to be modified during the manufacturing for oralAdministration.so that it will not be destroyed in the stomach.
  • 40. Mechanism of Action of penicillinPrevents cell wall synthesis by binding to enzymes called penicillin bindingproteins (PBPs). These enzymes are essential for the synthesis of the bacterialcell wall.- bactericidalPenicillin is more than just a drug. It is a symbol of introduction ofPharmacy.The name is common to everybody….presence of beta lactam ring in chemical structureweakens becterial cell wall = increase osmotic pressure = pull water in = lyses cellpcns, cephalosporins, related drugs
  • 41. mechanism of actionmechanism of action1.1. TheThe ββ-lactam binds to Penicillin Binding-lactam binds to Penicillin BindingProtein (PBP)Protein (PBP)2.2. PBP is unable to crosslink peptidoglycanPBP is unable to crosslink peptidoglycanchainschains3.3. The bacteria is unable to synthesize aThe bacteria is unable to synthesize astable cell wallstable cell wall4.4. The bacteria is lysedThe bacteria is lysed
  • 42. To understand the bactericidal action of penicillin one must know little bit about how bacteria look likeThe bacteria is a similar cell with the little arms and pili coming out the bacteria..…..The cell is having the cell membrane much like human cells, and it is also having a cell wall which isrigid coating around the membrane.There is a high pressure inside the cell i.e.. 10-20 atmosphere of pressure.It the cell wall is not there the rigid coating bacteria can burst. The water would continuously enter intothe cell as a result of osmotic pressure causing cell to swell and burst (lyses)
  • 43.  How They Work(penicillins)How They Work(penicillins) Antibiotics work by being eitherAntibiotics work by being either bactericidalbactericidal wherewherethey kill microorgnisms; or by beingthey kill microorgnisms; or by being bacteristaticbacteristaticwhere they inhibit thewhere they inhibit the growthgrowth of the microorganisms.of the microorganisms. An example of a bactericidal antibiotic isAn example of a bactericidal antibiotic is PenicillinPenicillin..This works byThis works by preventing the production of a substancepreventing the production of a substancethat form the cell wall:that form the cell wall: peptidoglycan.peptidoglycan. This means the cell will continue to growThis means the cell will continue to grow without dividingwithout dividingor developing new cell wall.or developing new cell wall. Therefore, the wall gets weaker, and eventuallyTherefore, the wall gets weaker, and eventuallyrupturesruptures (lysis).(lysis).
  • 44. Plasma membranePeptidoglycan cell wall(rigid coating around the membrane)Lipopolysaccharide layer(LPS)Gram +ve Gram –veThick ThinOne of the major difference between 2 types of bacteria is the amount of peptidoglyconThey have on the cell wall.Gram +ve bacteria has a lot of peptidoglycon and this actually holds the gram stain inThat’s why it is gram +ve.Gram –ve bacteria has a very thin layer of the peptidoglycon and gram stain leaks outCell membrane (or)Outer membraneSince the penicillins inhibits peptidoglycon synthesis it is much better an attacking gram+ve bacteria such asStaphylococci, and streptococci than gram –Ve bacteria like E-coli.
  • 45. (Cell membrane)(Peptidoglycan cell wall)One of the key composer of the bacterial cell wall isPeptidoglycon.THE PEPTIDOGLYCON MADE UP OF PEPTIDE ANDSUGAR UNITS.The structure of the wall consists of. Parallel series ofSugar back bones containg (NAM and NAG)N-acetylglucosamine andN-acetylmuramic acidalternate in a linear formCross linked by shortpeptides
  • 46. (Peptidoglycan cell wall)N-acetylglucosamineN-acetylmuramic acidN-acetylglucosamineandN-acetylmuramic acidare- transported across thecell membrane- glycosylated- incoroporated into thePeptidoglycan polymerCell membraneNAM AND NAG make a bunch or ropes which is then connects a shot peptideStrings to make a gird of the net. This grid make a cell strong.If you resist the bunch of ropes the pressurized bacteria can burst.
  • 47. (Peptidoglycan cell wall)N-acetylglucosamineN-acetylmuramic acidTranspeptidases locatedwithin the cell membraneare responsible forcross linking thePeptidoglycan chainsTranspeptidases(Penicillin Binding Proteins)In order to make the rigid grid,There is an enzyme calledTranspeptidase,which connects theLittle peptide strings perpendicularto the NAM and NAG chains.Cell membranePBP’S (or) transpeptidase help to buildOr construct maintain the peptidoglyconLayer.
  • 48. (Cell membrane)(Peptidoglycan cell wall)Penicillin’s inactivatethe transpeptidase enzymeby covalently bondingto the serine residueswithin the active siteBonding is by acetylationTranspeptidases(Penicillin Binding Proteins)SOPBP’S are present in bacterial cell membraneWhich are involved in the synthesis of cell wallBetalactum antibiotics (or)
  • 49. Chemically curious
  • 50. In human biochemistry there are onlyL-aminoacids,bacteria have racemaseenzymes that can convert L-amino acids into d-amino acids.In final stage of cell wallBiosynthesis, the peptide chanins arelinkedtogether by the displacement of D-alaninefrom one chain by glycine in another.aPBP’s(or)
  • 51. Ser LysNH3+Lys
  • 52. There is a high pressure inside the cell ( 10 to 20 atmospheric pressue presentInside the cell)If the cell wall is not there the rigid coating bacteria will burst.(water wouldContinuously enter in to the cell as a result of osmotic pressure causing cellto swell and burst(lysis)
  • 53. B-lactamases- Enzymes that catalyze the hydrolysis of the B-lactam ringthusinactivating the drug- Both membrane bound and secreted- Can be chromosomal or plasmid encodedONSOSNOHB-lactamaseDNA molecule that is separate from and can replicate indipendentlyOfbacteria produce enzyme beta lactamase* cleaves beta lactam ring & inactivates drug
  • 54. Eg; Staphylococcus aureusProduce a B-lactamase (Penicillinase)-Plasmid mediated-Secreted into the surrounding medium-Destroys the Penicillin before it can reach the PBP’sSOSOSO
  • 55. Gram –ve bacteria1. B-lactamases are cell associated and concentrated between the cellmembrane and the outer LPS layer thus effectively protectingthe PBP’s from the B-lactam Antibiotics2. LPS layer also impedes the entry of many Abx into the cell(Porin channels do exist but the ability to penetrate is dependent onmolecular size and ionic charge)SOSOSO(Lipo poly saccrahade layer)
  • 56.  Microbial resistance toMicrobial resistance to ββ-lactum antibiotics like-lactum antibiotics likepenicillins,cephalosporins occurs mainly due to the production ofpenicillins,cephalosporins occurs mainly due to the production ofan enzyme known asan enzyme known as ββ-lactamases.-lactamases. ββ-lactamases act by breaking the-lactamases act by breaking the ββ-lactum ring by catalyzing the-lactum ring by catalyzing thehydrolysis ofhydrolysis of ββ-lactum ring, which results in the loss of antibacterial-lactum ring, which results in the loss of antibacterialproperty of antibiotics. Thus micro-organisms exhibit resistance.property of antibiotics. Thus micro-organisms exhibit resistance. ββ-lactamase inhibitors are-lactamase inhibitors are ββ-lactum structures that have negligible-lactum structures that have negligibleantibacterial activity but inhibitantibacterial activity but inhibit ββ-lactamases.-lactamases. They can be administered along with penicillins to protect them fromThey can be administered along with penicillins to protect them fromββ-lactamases and broaden(increase) their spectrum of activity.-lactamases and broaden(increase) their spectrum of activity. ββ-lactamase inhibitors such as Clavalanic acid,sulbactam,Tazobactum-lactamase inhibitors such as Clavalanic acid,sulbactam,Tazobactumact as suicide substrates foract as suicide substrates for ββ-lactamase enzymes.-lactamase enzymes. Suicide substrates are agents which are converted to highly reactiveSuicide substrates are agents which are converted to highly reactivespecies when they ungergo an enzyme-catalyzed reaction. They formspecies when they ungergo an enzyme-catalyzed reaction. They formcovalent bonds to the enzyme and inhibit irreversibly.covalent bonds to the enzyme and inhibit irreversibly.
  • 57. ββ-lactum antibiotics-lactum antibioticsββ-lactum ring-lactum ringcontainshydrolysis Β-lactamasesINACTIVE COMPONDSΒ-lactamase enzyme + β-lactamse inhibitorcomplexEffectiveness of β-lactamase enzyme is diminished
  • 58.  Clavulanic acid:Clavulanic acid:clavalunic acid was isolated from streptomyces clavuligerus by Bechams inclavalunic acid was isolated from streptomyces clavuligerus by Bechams in1976.1976.It has weak and unimportant antibiotic activity, but it is powerful andIt has weak and unimportant antibiotic activity, but it is powerful andirreversible inhibitor of most betalactamases and as such it is now usedirreversible inhibitor of most betalactamases and as such it is now usedin combination with penicillins such as amoxicillinin combination with penicillins such as amoxicillin( Augmentin)( Augmentin) The structure of clavulanic acid was the first example of a naturally occruingThe structure of clavulanic acid was the first example of a naturally occruingbetalactam ring that was not fused to a sulfur-containing ring.betalactam ring that was not fused to a sulfur-containing ring. It is fused instead to an oxazolidine ring structure.It is fused instead to an oxazolidine ring structure.ESSENTIAL REQUIREMENTS FORESSENTIAL REQUIREMENTS FOR ββ-lactamase inhibition are:-lactamase inhibition are: StrainedStrained ββ-lactum ring.-lactum ring. Enol ether.Enol ether. The double bond of the enol ether has the Z configuration(Activity is reducedThe double bond of the enol ether has the Z configuration(Activity is reducedbut not eliminated if the double bond is E)but not eliminated if the double bond is E) No substitution at C-6No substitution at C-6 R- Stereochemistry at positions 2 and 5.R- Stereochemistry at positions 2 and 5. Carboxylic acid group.Carboxylic acid group.
  • 59.  The agents sulbactam and tazobactam haveThe agents sulbactam and tazobactam havealsobeen developed asalsobeen developed as ββ-lactamase inhibitors.-lactamase inhibitors. Sulbactum is combined with ampicillin in theSulbactum is combined with ampicillin in thepreparation calledpreparation called unasyn.unasyn. They to act as suicide substrates forThey to act as suicide substrates for ββ--lactamase enzymes.lactamase enzymes. Tazobactam is similar to sulbactam and it isTazobactam is similar to sulbactam and it isadministered Intravenously with piperacillin inadministered Intravenously with piperacillin inthe preparation calledthe preparation called Tazocin or ZosynTazocin or Zosyn.. Zosyn combination has broadest sectrum ofZosyn combination has broadest sectrum ofactivity of the theree combinations described.activity of the theree combinations described.
  • 60. B-lactamase InhibitorsAvailable agents B-lactamase binding PotencyClavulanic acid + + + + + +Sulbactam + + + + + +Tazobactam + + + + + + + +
  • 61. Combined with an expanded spectrum PenicillinAmoxicillin + Clavulanic acid = ClavulinTicarcillin + Clavulanic acid = TimentinPiperacillin + Tazobactam = TazocinAllow the “real” drug to get through to bind to the PBP’sRegain gram negative spectrum of activity otherwise lost dueto B-lactamase production
  • 62. Resistance to the B-lactam Antibiotics1. Differences in PBP’s- Decreased affinity of the PBP for the binding of the Abx- Increased production / concentration of PBP’s produced2. B-lactamase production- Spectrum of activity of various B-lactamases- Concentration of B-lactamases produced3. Decreased ability to penetrate to the PBP target- Primarily due to the LPS layer of gram –ve bacteria
  • 63.  Penicillin’s may be used to treat infectionsPenicillin’s may be used to treat infectionssuch as urinary tract infections.such as urinary tract infections. septicaemia, meningitis, intra-abdominalsepticaemia, meningitis, intra-abdominalinfection.infection. gonorrhoea, syphilis, pneumonia, respiratorygonorrhoea, syphilis, pneumonia, respiratoryinfections, ear, nose and throat infections.infections, ear, nose and throat infections. skin and soft tissue infections. Examples ofskin and soft tissue infections. Examples ofinfectious micro organisms (bacteria) that mayinfectious micro organisms (bacteria) that mayrespond to penicillin therapy includerespond to penicillin therapy include*Gonococci,* staphylococci*Gonococci,* staphylococci
  • 64.  *. Streptococcal infections*. Streptococcal infections*. Pneumococcal infections*. Pneumococcal infections*. Meningococcal infections*. Meningococcal infections*. Gonorrhea*. Gonorrhea*. Syphilis*. Syphilis*. Diphtheria*. Diphtheria*. Tetanus and gas gangrene*. Tetanus and gas gangreneDRUG OF CHOICE for *Anaerobic anthrax*DRUG OF CHOICE for *Anaerobic anthrax** actinomycosis* actinomycosis* Trench mouth* Trench mouth* Rat bite fever* Rat bite fever* Listeria monocytogenes* Listeria monocytogenes*Pasteurella multocida*Pasteurella multocida
  • 65.  Penicillins are available only with a prescription Penicillin’s are usefulPenicillins are available only with a prescription Penicillin’s are usefulagainst infections in many parts of the body, including the mouth and throat,against infections in many parts of the body, including the mouth and throat,skin and soft tissue, tonsils, heart, lungs, and ears. For example, dentistsskin and soft tissue, tonsils, heart, lungs, and ears. For example, dentistsoften prescribe penicillin to prevent infections after dental surgery.often prescribe penicillin to prevent infections after dental surgery. Biosynthetic penicillins are important in chemotherapy. TheyBiosynthetic penicillins are important in chemotherapy. Theyare used in treating streptococcal sore throat, tosillites,are used in treating streptococcal sore throat, tosillites,pneumococcal pneumonia, endocardites caused by somepneumococcal pneumonia, endocardites caused by somestreptococci, syphilis, gonorrhea, meningococcal infections andstreptococci, syphilis, gonorrhea, meningococcal infections andinfections that are caused by some anaerobic organisms.infections that are caused by some anaerobic organisms. The drug Augmentin, for example, contains a combination of amoxicillin(500mg) andThe drug Augmentin, for example, contains a combination of amoxicillin(500mg) anda beta-lactamase inhibitor, clavulanic acid (125mg)a beta-lactamase inhibitor, clavulanic acid (125mg)used in the treatment of feverish patients with neutropenia from cancer chemotherapy.used in the treatment of feverish patients with neutropenia from cancer chemotherapy.It is also useful in treating the sinusitis.It is also useful in treating the sinusitis.Animal/human bite wounds,otitis media in children.Animal/human bite wounds,otitis media in children. There are several types of penicillins, each used toThere are several types of penicillins, each used totreat different kinds of infections.treat different kinds of infections. These drugs will not work for, flu, and other infectionsThese drugs will not work for, flu, and other infectionscaused by viruses.caused by viruses.
  • 66.  Adverse/toxic effects of penicillins:-Adverse/toxic effects of penicillins:- Although most penicillins are safe for the majority of people,Although most penicillins are safe for the majority of people,some people may experience side effects.Once an individualsome people may experience side effects.Once an individualis allergic to one penicillin, he or she is most likely allergic tois allergic to one penicillin, he or she is most likely allergic toall of the penicillins.all of the penicillins. The most serious allergic reaction is anaphylaxis, a severeThe most serious allergic reaction is anaphylaxis, a severeallergic reaction that can cause skin rash, itching, difficultyallergic reaction that can cause skin rash, itching, difficultybreathing, shock, and unconsciousness.breathing, shock, and unconsciousness. An early sign of anaphylaxis is a feeling of warmth andAn early sign of anaphylaxis is a feeling of warmth andflushing. If any of these occurs, the medicine should beflushing. If any of these occurs, the medicine should bestopped and emergency help sought immediately.stopped and emergency help sought immediately. Anaphylactic shock occurs more frequently after parenteralAnaphylactic shock occurs more frequently after parenteraladministration but can occur with oral use.administration but can occur with oral use.
  • 67.  Less common side effects of penicillinsLess common side effects of penicillinsare:-are:- 1.Nausea 2.Diziness 3.Head ache 4.skin rashes1.Nausea 2.Diziness 3.Head ache 4.skin rashes5.Bronchospasm 6. vasculitis 7. inflammation of5.Bronchospasm 6. vasculitis 7. inflammation ofblood vessles 8.constriction of the airways of theblood vessles 8.constriction of the airways of thelungs 9.fever 10. Angio odema or swelling of lips,facelungs 9.fever 10. Angio odema or swelling of lips,faceand tongue.and tongue. Other most common side effects are mild diarrhea,Other most common side effects are mild diarrhea,vomiting, headache, vaginal itching and discharge,vomiting, headache, vaginal itching and discharge,sore mouth or tongue, or white patches in the mouthsore mouth or tongue, or white patches in the mouthor on the tongue. These problems usually go away asor on the tongue. These problems usually go away asthe body adjusts to the drug and do not requirethe body adjusts to the drug and do not requiremedical treatment unless they continue or they aremedical treatment unless they continue or they arebothersome.bothersome. Occasionally, certain types of penicillin may causeOccasionally, certain types of penicillin may causethe tongue to darken or discolor. This condition isthe tongue to darken or discolor. This condition istemporary and will go away when the medicine istemporary and will go away when the medicine is
  • 68.  Effect on GITEffect on GIT: Broad spectrum penicillins: Broad spectrum penicillinslike ampicillin, when administered orally, alterslike ampicillin, when administered orally, altersthe bacterial flora in the intestines and leads tothe bacterial flora in the intestines and leads toGIT disturbances like diarrhoeaGIT disturbances like diarrhoeaOn rare occasions some types of penicillin may cause severe abdominal or stomachcramps, pain, or bloating or severe or bloody diarrhoea. Other rare side effectsinclude fever, increased thirst, severe nausea or vomiting, unusual tiredness orweakness, weight loss, seizures, or unusual bleeding or bruisingOverdosage/Acute Toxicity - Acute oral penicillin overdoses are unlikely tocause signif­icant problems other than GI distress, but other effects arepossible .In humans, very high dosages of parenteral penicillin’s, especially inpatients with renal disease, have induced CNS effects.
  • 69.  1.1. Hypersensitivity or allergic reactionsHypersensitivity or allergic reactions :: Hypersensitivity to penicillin’s is caused by the.Hypersensitivity to penicillin’s is caused by the.degradation products of penicillins.Thedegradation products of penicillins.Thedegradation products of penicilloicdegradation products of penicilloicacid,sodium benzylpenicilloate (ofacid,sodium benzylpenicilloate (ofbetalactum ring) binds ie combines to serumbetalactum ring) binds ie combines to serumproteins initiating an IgE and initiates the IgEproteins initiating an IgE and initiates the IgEmediated inflammatory reactionsmediated inflammatory reactions It occurs in about 5-8% of the patients and accordingIt occurs in about 5-8% of the patients and accordingto estimation, 300-500 people have been dieing eachto estimation, 300-500 people have been dieing eachyear form penicillin induced anaphylaxis.year form penicillin induced anaphylaxis. Hypersensitivity reactions are classified intoHypersensitivity reactions are classified into A) Immediate HypersensitivityA) Immediate Hypersensitivity b) Accelerated Hypersensitivityb) Accelerated Hypersensitivity C) Late HypersensitivityC) Late Hypersensitivity
  • 70.  A)A) Immediate hypersensitivityImmediate hypersensitivity : -: - ThisThisoccurs within 20 min. of parenteraloccurs within 20 min. of parenteraladministration of penicillin and is characterizedadministration of penicillin and is characterizedby the prurities, skinrashes, wheezing, rhinitis,by the prurities, skinrashes, wheezing, rhinitis,sneezing These reactions are transformed in tosneezing These reactions are transformed in toanaphylaxis (extreme from of immediateanaphylaxis (extreme from of immediatehypersensitivity reaction) theat is characterisedhypersensitivity reaction) theat is characterisedby hypotensive shock, angioneurotic oedema,by hypotensive shock, angioneurotic oedema,choking, loss of consciousness and finallychoking, loss of consciousness and finallydeath Serious anaphylaxis reactions requiredeath Serious anaphylaxis reactions requireimmediate emergency treatment withimmediate emergency treatment withephedrine, oxygen, IV steroids and airwayephedrine, oxygen, IV steroids and airwaymanagement, including intubations should alsomanagement, including intubations should alsobe administered as indicatedbe administered as indicated
  • 71.  B)B) Accelerated HypersensitivityAccelerated Hypersensitivity : - It: - Itoccursoccurs within 72 hourswithin 72 hours after penicillin hasafter penicillin hasbeen administered. Acceleratedbeen administered. Acceleratedhypersensitivity reactions are characterized byhypersensitivity reactions are characterized byskin rashes,fever,urticaria,angioneuroticskin rashes,fever,urticaria,angioneuroticoedema. Death is a rare consequence.oedema. Death is a rare consequence. c)c)Late HypersensitivityLate Hypersensitivity : It occurs: It occurs after 72after 72hourshours after penicillin has been administered.after penicillin has been administered.This reaction is mediated by IgE and IgMThis reaction is mediated by IgE and IgMantibodies and manifested byantibodies and manifested by utricaria,skin rashes similar to measles.localutricaria,skin rashes similar to measles.localinflammation, serum sicknessinflammation, serum sicknessandcoomb’spositive haemolytic anaemiaandcoomb’spositive haemolytic anaemia
  • 72. Penicillins advantages and disadvantagesPenicillins advantages and disadvantages Penicillins disadvantagesPenicillins disadvantages :: acid liability - most of these drugs are destroyed by gastric acidacid liability - most of these drugs are destroyed by gastric acid short duration of action - because of this short half-life, the penicillins must beshort duration of action - because of this short half-life, the penicillins must beadministered at short intervals, usually every 4 hoursadministered at short intervals, usually every 4 hours lack of activity against most Gram-negative organismslack of activity against most Gram-negative organisms drug hypersensivity - about 10% of population has allergydrug hypersensivity - about 10% of population has allergy many patients experience GI upsetmany patients experience GI upset painful if given intramuscularlypainful if given intramuscularlyPenicillins advantagesPenicillins advantages :: bactericidal against sensitive strainsbactericidal against sensitive strains relatively nontoxicrelatively nontoxic have excellent tissue penetrationhave excellent tissue penetration efficacious in the treatment of infectionsefficacious in the treatment of infections relatively inexpensive in comparison with other antibiotics.relatively inexpensive in comparison with other antibiotics. Newer penicillins are resistant to stomach acid, such as penicillin V, or have aNewer penicillins are resistant to stomach acid, such as penicillin V, or have abroader spectrum, such as ampicillin and amoxicillinbroader spectrum, such as ampicillin and amoxicillin
  • 73. Since the advent of Penicillin in 1945there have been great advancesmade in the realm of anti-infective agentsAntibioticsAntiviralsAntifungalsAntiparasitics
  • 74. PenicillinAmpicillinImipenemDoxycyclineAzithromycinClarithromycinMetronidazoleCeftriaxoneCephalexinCefuroximeVancomycinSynercidMoxifloxacinGatifloxacinCloxacillinPiperacillinTetracyclineRifampinNitrofurantoinSeptraAmikacinCefepimeCiprofloxacinGentamicinClindamycinLinezolidErythromycinSulfadiazineAztreonam