penicillins by dr. panchumarthy ravisankar m.pharm., ph.d

PENICILLINS

1PENICILLINS

IntroductionHistorical backgroundClassificationBiological sources & Nomenclature Basic structure & SARStructures of different PenicillinsChemical degradation & BiosynthesisMechanism of actionTherapeutic uses & ToxicityAdvantages & DisadvantagesByDr. Panchumarthy Ravisankar M.Pharm, Ph.D.

K. ManjushaVignan Pharmacy CollegeVadlamudi -522 213.Guntur DistAndhra PradeshINDIA.

1

CONTENTS:IntroductionHistorical backgroundClassificationBiological sources & Nomenclature Basic structure & SARStructures of different PenicillinsChemical degradation & BiosynthesisMechanism of actionTherapeutic uses & ToxicityAdvantages & Disadvantages

Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)2

INTRODUCTION:

The term antibiotic came from the word antibiosis coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life.Defined as chemical substances produced by various species of microbes such as bacteria & fungi, in low concentrations destroy or inhibit the growth of other species of microbes. Anti = against Bios = life


3

Antibiotics are classified based on structure, spectrum, source & pharmacological activity.Based on the structure antibiotics are of different types like lactams, Aminoglycosides, Tetracyclines, Macrolides, polypeptides, Quinolines, Sulfa antibiotics & miscellaneous.PENICILLINS comes under -LACTAM CLASS OF ANTIBIOTICS.


Antibiotics are classified based on structure, spectrum, source & pharmacological activity.Based on the structure antibiotics are of different types like lactams, Aminoglycosides, Tetracyclines, Macrolides, polypeptides, Quinolines, Sulfa antibiotics & miscellaneous.PENICILLINS comes under -LACTAM CLASS OF ANTIBIOTICS.


Antibiotics are classified based on structure, spectrum, source & pharmacological activity.Based on the structure antibiotics are of different types like lactams, Aminoglycosides, Tetracyclines, Macrolides, polypeptides, Quinolines, Sulfa antibiotics & miscellaneous.PENICILLINS comes under -lactam class of antibiotics.


HISTORICAL BACKGROUND OF PENICILLINSIn 1928 ALEXANDER FLEMMING discovered penicillin from the fungus Penicillium notatum.Observed that colonies of S. aureus failed to grow in the areas contaminated by Penicillium notatum.He isolated the mould, grew it in a fluid medium and found that it produced a substance capable of killing many of the common bacteria that infect humans.He coined the term PENICILLIN.


It was unstable and he was unable to purify.FLOREY & CHAIN used Freeze drying & Chromatography to isolate penicillin & shared the Noble prize with Fleming.In June 1948 penicillin was available to treat 10 patients.After fermentation research 2.3 million doses had been increased in U.S.


CLASSIFICATION OF PENICILLINS

sourceRoute of administrationBased on spectrum of activityResistant to hydrolyzing enzymeResistant to acids1.Natural 1.Oral 1.Narrow spectrum 1.Resistant to 1.Acid Penicillin G Amoxycillin Methicillin beta lactamase stable Peniciilin V Oxacillin Oxacillin Methicillin PenicillinG2.Biosynthetic Cloxacillin Dicloxacillin Oxacillin Oxacillin Penicillin G Dicloxacillin Nafcillin Cloxacillin Cloxacillin Penicillin V Ampicillin 2.Broad spectrum Dicloxacillin Ampicillin Penicillin X Ampicillin 2.Non resistant 2.Acid Penicillin F 2.Parenteral Amoxycillin to beta lactamase unstable Penicillin K Penicillin G 3.Intermediate spectrum Penicillin G Ticarcillin3.Semisynthetic Methicillin Penicillin G Penicillin V Methicillin Oxacillin Nafcillin Penicillin v Ampicillin Piperacillin Cloxacillin Carbencillin 4.Extended spectrum Amoxycillin Dicloxacillin Ticarcillin Carbencillin Carbencillin Ampicillin Ticarcillin Methicillin Azocillin Mezlocillin9

BIOLOGICAL SOURCES OF PENICILLINS:Benzyl penicillin obtained by fermentation from Penicillium notatum.Now it is from a high yielding strain Penicillium chrysogenum. NOMENCLATURE1. Chemical Abstract System (CAS):

6-acylamino-2,2-dimethyl-3carboxylic acid Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)106-acylamino-2,2-dimethyl-3-carboxylic acid.

10

2.United states pharmacopoeia:Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)11 4-Thia-1-aza-bicyclo[3.2.0] heptaneReverse of CAS system.3.As derivatives of Penam:PENAM - Unsubstituted bicyclic system with carbonyl group.

4.As derivatives of Penicillanic acid:Penicillins are named as derivatives of Penicillanic acid ring system with 2,2-dimethyl and carboxyl group as substituents at 2nd and 3rd positions.


6-Amino penicillanic acid

5.As derivatives of penicillin:(on the basis of R group) TRIVAL SYSTEM

6-carbonyl amino penicillanic acid portion of the molecule is named as penicillin.This system is simple and serves as a good measure for naming and comparing closely related penicillin structures.Not well suited for compounds having the ring modified derivatives.



Basic structure of Penicillin:


Acyl amino side chain

6-Amino penicillanic acid

Methyl groups

15

Shape of the molecule is like a Half open book.Has 3 chiral centers at C-3 , C-5 ,C-6.Disruption of these lead to loss of activity.Acyl amino side chain is essential for biological activity.Variable group R determines the stability and improved spectrum of activity.Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)16


STRUCTURAL ACTIVITY RELATIONSHIP :1234567

Structures of different Penicillins:Penicillin G:Acid unstable.Parenteral route.Self destructive mechanism in its structure because of influence of acyl side chain.Has gram positive potency against susceptible Staphylococci, Streptococci.


18

Penicillin V:

More acid stable then Penicillin G.Administered by oral route.Has electronegative oxygen on the acyl side chain with electron withdrawing effect which has the ability to solve acid sensitivity.Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)19

Methicillin:

Has no electron withdrawing group on the side chain.Acid sensitive and has to be injected.Steric shields can be added to penicillins to protect from penicillinase enzyme.Bulky groups on the side chain prevent the penicillinase enzyme to reach the penicillinase active site.


O

N

SNH

COOHCH3CH3

CO

Isoxazolyl Penicillins

ON

CH3

R1

R2

R1 R2

OxacillinH HCloxacillinCl HDicloxacillinCl Cl

Better penicillinase resistant agents have been developed.The isoxazolyl ring acts as the steric shield butIt is also electron-withdrawing giving the Structure acid stability.

Flucloxacillin Cl FBulky and electronwithdrawing

Isoxazolyl penicillins:Penicillinase resistant penicillins.Ring acts as steric shield and also a electron withdrawing group giving acid stability to the structure. R1 R2 Oxacillin H H Cloxacillin Cl H Dicloxacillin Cl Cl Flucloxacillin Cl FVignan Pharmacy College,Vadlamudi,Guntur.(A.P)22

22

Ampicillin:

If hydrophilic groups like (NH2, OH , COOH ) are attached to the carbon that is to the carbonyl group on the side chain then hydrophilic group aids the passage of penicillins through porins of gram ve bacteria.Susceptable to degradation of penicillins.Hence given in combination with lactamase inhibitors like Sulbactum ,Gentamycin.


Amoxycillin:

hydroxy ampicillin.Better absorbed through gut wall due to presence of hydroxyl goup.Same spectrum of activity as that of penicillin G but more active against gramve bacteria.Acid resistant hence given orally.Non toxic.


Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)25 R R

Nafcillin Ticarcillin

Carbenicillin Piperacillin

Chemical degradation:Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)26

-CO2HeatHgCl2 / Water+Strong acid


CH3OHHgCl2 / Water+dil.acidpH 2


pH 4H2O+H+-CO2

Enzymatic hydrolysis with Penicillinase or lactamase:Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)29

Enzymatic hydrolysis with Amidase:

Synthesis of Penicillins from 6-APA:Production of 6-APA: Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)30

Synthesis of Penicillin G from 6-APA:Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)31

Bacteristatic Antibiotics Bactericidal Penicillins Inhibit the synthesis of peptidoglycon layer containing NAM &NAG connected by penicillin binding proteins(PBP) Acts on PBP and inhibits the synthesis of Peptidoglycon.

Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)32Mechanism of action:

Gram +ve Gram -veCell membranePeptidoglycon cell wallLipopolysaccharide layer

32


(Peptidoglycan cell wall)

N-acetylglucosamineN-acetylmuramic acid

Transpeptidases locatedwithin the cell membraneare responsible for cross linking thePeptidoglycan chainsTranspeptidases(Penicillin Binding Proteins)

In order to make the rigid grid, There is an enzyme called Transpeptidase,which connects the Little peptide strings perpendicular to the NAM and NAG chains.Cell membranePBPS (or) transpeptidase help to build Or construct maintain the peptidoglyconLayer.

(Cell membrane)(Peptidoglycan cell wall)

Penicillins inactivatethe transpeptidase enzymeby covalently bondingto the serine residues within the active site.

Bonding is by acetylationTranspeptidases(Penicillin Binding Proteins)

S

O

PBPS are present in bacterial cell membraneWhich are involved in the synthesis of cell wallBetalactum antibiotics (or)

Beta lactamase Inhibitors:

Has negligible antibacterial activity.Given with Penicillins which increases spectrum of activity.Microbial resistance to beta lactam antibiotics.


lactam antibiotics lactam enzyme + lactamase inhibitor

Contain lactum ring Complex Catalysing the lactamases hydrolysis of lactum ring Effectiveness of lactamase is diminished INACTIVE COMPOUNDS

Enhances the activity of lactam antibioticsVignan Pharmacy College,Vadlamudi,Guntur.(A.P)37

Clavulanic acid:Isolated from Streptomyces clavuligerus.1st naturally occuring lactum ring that was not fused to a S containing ring. Sulbactum:

lactamase disabiling agent.Prepared by partial chemical synthesis from penicillins.Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)38

Tazobactum:Co-administered with Piperacillin.Has little or no antibacterial activity.


Beta lactamase Inhibitors:

Available agents -lactamase binding Potency

Clavulanic acid + ++ + + +

Sulbactam + + + + + +

Tazobactam + + + + + + + +

Combinations of penicillins with lactamase inhibitors:Amoxicillin+ Clavulanic acid = ClavulinTicarcillin+ Clavulanic acid = TimentinPiperacillin + Tazobactam= TazocinAmpicillin + Sulbactum = Unasyn


Therapeutic uses:Skin & soft tissue infections.Diphtheria, tetanus, gas gangrene.Intra abdominal infection, syphilis. Ear, nose, lungs infections.Streptococcal infections.Drug of choice for Anthrax, Trench mouth, Rat bite fever, Actinomycosis.Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)41

Ampicillin & Amoxycillin HELPS to clear Enterococci infections. H- Heamophilus Influenzae E- Escherichia coli L- Listeria monocytogene P- Proteus mirabilis S- Salmonella typhiVignan Pharmacy College,Vadlamudi,Guntur.(A.P)42

Toxicity of Penicilins:Some people experience side effects.Serious allergic reaction is Anaphylaxis which is fatal.Broad spectrum antibiotics like Ampicillin by oral route alters flora in intestine and leads to GIT disturbances.High dosages of parenteral penicillins in renal patients has induced CNS effects. Nausea, dizziness, bronchospasm, sore mouth & tongue, skin rashes, angio odema.


Hypersensitivity or Allergic reactions:Caused by degradation products of penicillin.3 types of hypersensitivity. Vignan Pharmacy College,Vadlamudi,Guntur.(A.P)44 Immediate Accelerated LateOccurs within 20minsWithin 72 hrsAfter 72 hrsPrurities,skin rashes,Wheezing, sneezing, rhinitisSkin rashes, fever, angioneurotic oedema, utricaria+ve heamolytic anemia, utricaria, skin rashes, local inflammation, serum sickness


Advantages:Have excellent tissue penetration.Bactericidal against sensitive strains.Relatively nontoxic. Efficacious in the treatment of infections. Inexpensive in comparision with other antibiotics. Newer penicillin's are resistant to stomach acid, such as penicillin V, or have a broader spectrum, such as ampicillin and amoxicillin.


Disadvantages:Acid liability - most of these drugs are destroyed by gastric acid Lack of activity against most Gram-negative organisms.Short duration of action - because of this short half-life, the penicillin's must be administered at short intervals, usually every 4 hours. Drug hypersensitivity - about 10% of population has allergy. Many patients experience GI upset. Painful if given intramuscularly.


Keypoints:Penicillins have a bicyclic structure consisting of a -lactam ring fused to a thiazolidine ring.Strained -lactam ring reacts irreversibly with the transpeptidase enzyme responsible for the final cross-linking of the bacterial cell wall.Penicillin analogues can be prepared by fermentation or by a semi-synthetic synthesis from 6-APA.


Variation of the penicillin structure is limited to the acyl side chain. Penicillins can be made more resistant to acid conditions by incorporating an electron-withdrawing group into the acyl side chain.Steric shields can be added to penicillins to protect them from bacterial -lactamase enzymes.Broad-spectrum activity is associated with the presence of an -hydrophilic group on the acyl side chain of penicillin.


CONCLUSIONPenicillin antibiotics were among the first medications to be effective against manybacterial infectionscaused bystaphylococciandstreptococci & are still widely used today though many types of bacteria have developedresistance.About 10% of people report that they areallergicto penicillin; however, 90% of this group are not actually allergic.There are several enhanced penicillin families which are effective against additional bacteria; these include the antistaphylococcal penicillins,aminopenicillins&antipseudomonal penicillins.


References:William O. Foye, Textbook of Medicinal Chemistry, Lea & Febiger, Philadelphia. Pg no: 1046 1059JH Block & JM Beale, Wilson & Giswolds Textbook of Organic Medicinal Chemistry & pharmaceutical chemistry by (Eds), 11th Ed, Lipincott, Raven, Philadelphia,2004Sriram, Medicinal Chemistry. Pg no: 294-395Kadam, Textbook of Medicinal Chemistry. Pg no: 120-131 Ilango, Principles of Medicinal chemistry(vol.1). Pg no: 5.2-5.10G.L.Patrick, Introduction to Medicinal Chemistry. Pg no:429-453



penicillins by dr. panchumarthy ravisankar m.pharm., ph.d

Education