M pharmacy pharmacology

1. Cellular and molecular mechanism of actions and resistance
of antimicrobial agents – Beta-lactams
Submitted by: Paradhe Ayodhya Submitted to: Behere sir
M pharm 1st year ( pharmacology) (pharmacology department)
Sudhakar Rao Naik Institute of Pharmacy Pusad

2. Contents:
1. Introduction
 Beta- lactam
 Classification of penicillin
 History
 Natural penicillin
 semisynthetic penicillin
2. Biosynthesis of bacterial cell wall
3. Mechanism of action of Beta –lactam
4. pharmacokinetics, uses and ADR of Beta- lactam antibiotics
5. Beta lactamase inhibitors
6.Cephalosporin

3.  Introduction:
Beta-lactam:
Beta-lactam antibiotics are those drugs that contain B- lactam in their ring structure.
Widely produced and used antibacterial drugs in world.
Bacterisidal in nature.
It divided into several classes based on their structure and function; but all class have
common beta lactam ring structure.
All drugs of this class acting by inhibiting cell wall synthesis in bacteria. These active
against multiplication of bacteria only.
Different class of drugs are:
1. Penicillin
2. Beta-lactamase inhibitors
3. Cephalosporin Beta-lactam structure
4. Monobactams
5. Carbapenems

4.  Classification of penicillin:

5.  History:
 1928: alexander Fleming discovered mold which inhibits growth of staphylococcus
bacteria
 1940: penicillin isolated and tested on mice by research at oxford
 1941: penicillin mass produce by fermentation for use by us soldiers in WWI
 1950: 6-APA discovered and semisynthetic penicillis developed.
 1960: novel beta- lactams / beta- lactamase inhibitors discovered and modified from
natural product of bacteria.
 Penicillin:
First antibiotic used clinically in 1941
This is natural dextrorotatory penicillin-G
Aquous penicillin-G- drug of choice for neurosyphilis.
Valin is biosynthetic precursor for natural penicillin
It obtain from:
First time – penicillium notatum
Commercially- penicillium chrysogenum

6. Penicillin nucleus consist of fused thiazolidine and beta- lactam ring which side chain
attached through amide linkage.
Structure:
Ring A- lactam ring
Ring B- thiazolidine
Natural penicillin: penicillin-G also called as benzyl penicillin
It is natural, thermolabile, acid labile and highly water soluble
It stable in dry state but solution deteriorate rapidly at room temperature.
Stable at 4 degree celsius.
Preparation of natural penicillin:
Sod. Penicillin, procaine penicillin, benzathine penicillin-G

7.  Biosynthesis of bacterial cell wall:
 Bacterial cell wall is cross linked polymer called peptidoglycan which allows bacteria to
maintain it shape despite the internal turgor pressure cased by osmotic pressure difference.
 If peptidoglycan fails to cross link cell wall lose it strength which result cell lysis.
 Peptidoglycan is carbohydrate composed of alternative units of NAMA and NAGA.
 NAMA units have peptide side chain which crossed linked from L- Lys residue to terminal
D-Ala- DAla link on neighbouring NAMA unit.
 This done in directly gram –ve bacteria via pentaglycine on L- lysin residue in gram + ve
bacteria
 Cell wall synthesis starts by conversion of UDP-N- acetylglucosamine(UDP-G) to UDP-N-
acetylmuramic acid (UDP-M) in the presence of enzyme enolpyruvate transferase
 UDP- is then acquire pentapeptide
 Alanin racemase and alanin-alanin ligase helps in formation of pentapeptide unit.
 UDP is then removed from UDP-M pentapeptide by bactoprenol and N- acetylglucosamine
is added to it.
 The resulting molecule formed is transported across the plasma membrane by bactoprenol

8.  Elongation of peptidoglycan chain occurs with the help of enzyme transglycosylase
 Strength to peptidoglycan chains is provided by cross linking of elongated chains
with the help of transpeptidase.

9.  Mechanism of action:
All beta- lactams drugs are bacteriocidal in nature, they inhibits the cell wall synthesis
of bacteria.
These drugs are more effective for gram + ve bacteria because they have thick
peptidoglycan layer between outer layer and cytoplasmic membrane.
Only hydrophilic penicillin can diffused through porin channels.
This drug binds to specific receptors of bacterial cell membrane (PBP)
Inhibit transpeptidase and carboxypeptidase ( enzyme responsible for cross
linking of peptidoglycan chain)
so cross-linking of cell wall does not occurs
bacteria form in the presence of these drugs are without cell wall and die due to an
imbalance of water

10.  Bacterial resistance to penicillin:
1. Modification of PBP in cell membrane- high molecular weight PBPs has decrease
affinity for antibiotics eg. Streptococcus pneumoniae
2. Inability of drugs to penetrate to its site of action.- in gram – ve bacteria contain
porins in outer membrane wich impermeable to antibiotics
3. Beta – lactamase produced by gram – ve and gram + ve bacteria – inactivation of
beta- lactam antibiotics by opening of beta- lactam ring
Producing penicillinase which destroy beta- lactam ring
4. Active efflux pump- efflux increase eg. E. coli
5. Inactive influx
6. Alternative pathway in cell wall synthesis
7. Enzyme production
8. Metabolite action

11.  Pharmacokinetics:
 Penicillin are acid labile also interfere absorption
 Given I.M. and I.V. route
 Plasma t-half – 30min
 Orally administration; destroy by gastric acid
 Duration- 4-6 hrs
 Plasma albumin binding (65%)
 Excreted in urine mainly by tubular secretion, GF.
 Widely distributed in body
 It not cross BBB but in meningeal infection it crosses
 Combination of penicillin+ probencid: probencid competes fir renal tubular
secretion and there by prolongs duration of action of penicillin.

12.  Uses of penicillin:
1. Bacillus ( anthrax)
2. Streptococcal infection
3. Pneumococcal infection
4. Meningococcal infections
5. Gonorrhoea
6. leptospirosis- rat bite fever
7. Tetanus and gangrene
8. Prophylactic uses:
a) Rheumatic fever
b) Bacterial endocarditis
9. Treponema pallidum, tetanus
10. Gas gangrene- blood supply stop at any area of body part

13.  Adverse effect of penicillin:
1. Anaphylactic reaction most common
2. Minor reaction:
a) Oral- nausea and vomiting
b) IM- local pain, erythema
c) iv- P-G thrombophlebitis
d) Iv procain PG – anxiety, mental disturbance, seizure due to procain.
e) Intrathecal route- cause arachnoiditis, convulsion
3. Hypersensitivity reaction: skin rashes, fever, bronchospasm, joint pain,
dermatitis, anaphyalactic shick
4. Anaphyalaxis- begin within few min. after administration of penicillin.
It characterized by: acute cv collaps, branchospasm and hypotention,
angioedema(larynx)

14.  Beta- lactamase / penicillinase inhibitors:
Is family of enzyme produced by many gram + ve bacteria.
That inactivate Beta- lactam antibiotics by opening of Beta – lactam ring.
Three inhibitors of Beta- lactmase:
1.Clavulanic acid
2. Sulbactam use only in combination with penicillin and
cephalosporins.
3. Tazobactam
1. Clavulanic acid:
It obtained from streptomyces clavuligerus.
It inhibits a wide veriety ( class 2 to 5) gram + ve and gram – ve bacteria.
It is progressive inhibitors because inhibition increase with time, also called “suicide
inhibitor” because it gets inactivated after binding to the enzyme.
Clavulanic acid + amoxycillin co-amoxycyar
D.O.C. for gonorrhoea

15. Clavunalates permeates the outer layers of cell wall of gram – ve bacteria and
inhibits periplasmically located beta- lactmases.
Pharmacokinetics:
has rapid oral absorption
Bioavailability- 60%
Eliminate mainly by glomerular filtration
It largely hydrolysed and decarboxylated before excretion while amoxicillin is
primarily excreted unchanged by tubular secretion.
Uses:
Addition of clavulanic acid re- established activity of amoxicillin against B-
lactamases producing resistants staph. Aureus, H. influenzae, N. gonorrhoeae,
E.coli, Salmonella typhi.
In combination- bact. Fragilis and branhamella catarrhalis

16. Co- amoxiclave is indicated for empirical therapy of:
1. Skin and soft tissue infection
2. Intraabdominal and gynaecological sepsis
3. urinary, biliary and respiratory tract infection
4. gonorrhoea- single dose amoxicilin3gm + clavulanic acid 0.5gm+ probencid 1gm is
curative.
Adverse effect:
Candida stomatitis, vaginititis and rashes
Some cases hepatic injury
2. Sulbactam :
It is semisynthetic Beta- lactamase inhibitors
related chemically as well as activity to clavulanic acid
Progressive inhibitors highly active against class2 and 5 but poor active against 1
2-3 times less potent than clavulanic acid
Ampicilin + sulbactam sultamicin effective against Beta-
lactamase

17. Oral absorption inconsistent so given parentrally
Uses:
1. PPNG gonorrhoea- inhibit N. gonorrhoeae
2. Mixed aerobic, anaerobic infection
3. Intra abdominal gynaecological, surgical and skin /soft tissue infections
Adverse effect:
Pain at site of injection
Thrombophelbitis of injected vein
Rash, diarrhoea.
3. tazobactam:
Similar to sulbactam
Piperacilin+ tazobactam used in sever infection – peritonitis, pelvic/
urinary/respiratory infection caused by Beta – lactamase producing bacilli.

18. Combination not active against piperacillin – resistant pseudomonas
Given by I.V.
Effective against extended-spectrum lactamase.
 Cephalosporin:
Group of semisynthetic antibiotics derived from cephalosporin c.
Obtained from fungus cephalosporium
chemically related to penicillin
Nucleus consists of B- lactam ring fused with a dihydrothiazine ring by the addition of
different side chains at position 7 of B-lactam ring and a large no. of semisynthetic
compound have been produced.
All are bactericidal in nature.
Their mechanism of action is similar to penicillin. i.e. inhibition of bacterial cell wall
synthesis.
Resistance: same as penicillin S

19. Classification of cephalosporins:

20. Pharmacokinetics:
To be injected
Excreted rapidly by kidney
Clinical uses:
Cefazolin is the d. o. c for the surgical prophylaxis
Cefotetan, cefmetazole and cefoxitin are active against anaerobes like bacteriodes
fragilis
Ceftazidime + aminoglycosides d. o. c. for the pseudomonas infection
Ceftriaxone is the first d. o. c. for gonorrhoea
Adverse effect:
Diarrhoea, hypersensitivity reaction
Nephrotoxicity- highest with cephaloridine
Bleeding
Ceftazidime cause neutropenia and thrombocytopenia

21. References:
1. KD Tripathi essential of medical pharmacology
2. Satoskar book of pharmacology
3. The pharmacological basis of therapeutics- goodman and gill man’s
4. Pharmacology by H. P. Rang and Dale.

22. THANK YOU!