This document discusses penicillin, the first antibiotic discovered by Alexander Fleming in 1928. It was first extracted from the Penicillium mold. Later, Penicillium chrysogenum was found to give the highest yield and is now used to produce penicillin via fermentation. The main types discussed are penicillin G, acid resistant penicillins, penicillinase resistant penicillins, and extended spectrum penicillins. The document covers the mechanism of action, uses, advantages, disadvantages, and side effects of various penicillin derivatives.

1. Jayendra N Chaudhary
M Pharm (Pharmacology)*
L M College of Pharmacy
Amadavad,Gujrat1,

2. Introduction
 Penicillin is the first antibiotic
discovered by Alexander Flamming in
1928.
 First extracted from Penicillium
notatum.
 Later on, Penicillium chrysogenum was
found to give highest yield and is now
used to obtain penicillin by bio-
fermentation process.
 The penicillin obtained from the P.
chrysogenum is penicillin-G or benzyl
penicillin.
2

3.  In 1930, Cecil George Paine, a pathologist treated
ophthalmia neonatorum, a gonococcal infection in
infants and achieved the first recorded cure with
penicillin.
 In 1939, Australian scientist Howard Florey and a team of
researchers made progress in showing the in vivo
bactericidal action of penicillin.
 In 1940 they showed that penicillin effectively cured
bacterial infection in mice.
 By late 1940, the Oxford team under Howard Florey had
devised a method of mass-producing the drug, but yields
remained low.
 Florey and Chain shared the 1945 Nobel Prize in Medicine
with Fleming for their work
3

4. 4

5. 5

6. MECHANISM OF ACTION
 Inhibits bacterial cell wall synthesis
 Inhibits the enzyme transpeptidase that brings about
cross-linking between 5th glycine of the already
existing peptidoglycan and 4th amino acid of the newly
formed peptidoglycan
 In this way, synthesis of peptidoglycan, a component
of cell wall providing rigid mechanical stability, is
inhibited.
 Bactericidal in action
 In its presence , bacterial cell wall becomes soft and
finally undergoes lysis
 More effective on actively multiplying organisms
6

7. 7

8. 8

9. 9

10.  There are additional, related targets for the action of
penicillin. These are collectively termed as Penicillin
Binding Proteins(PBPs).
 All bacteria have several such entities ;
for example S. aureus - 4 PBPs
E.coli- at least 7 PBPs
 The higher mol.wt.PBPs of E.coli include
transpeptidase while other include those that are
necessary for maintenance of rod-like shape of
bacterium and for septum formation at division.
 Hence inhibition of the activities of other PBPs may
cause delayed lysis or the production of long ,
filamentous forms of bacterium.
10

11. 11

12. Anti-bacterial spectrum
Gram +ve
Staphylococci
Streptococci
Pneumococci
Enterococci
C.diptheriae
C.tetani
B.subtilis
B.anthracis
Gram -ve
Gonococci
Meningococci
Miscellaneous
microbes
Treponema pallidum
Listeria
monocytogenes
Spirillum minor
Leptospira
Actinomyces
12

13. PHARMACOKINETIC
 On oral administration, it is absorbed from duodenum.
 Easily destroyed by gastric acid and food interferes with its
absorption. Thus, it should be given 30 min prior or 2-3 hrs.
after meals.
 Peak concentrations are achieved within 30-60 min.
 If given through IM route, peak levels are achieved within 15-30
min.
 Plasma protein binding-60%
 High concentrations in kidney, liver, intestine and skin
 Better distribution in infected tissues
 Metabolism:30%in liver.70% is excreted unchanged by tubular
secretion
 Eliminated within 3-4 hrs. 13

14. THERAPEUTIC USES
 Pneumococcal infections-pneumonia ,emphysema ,pericarditis , meningitis
 Streptococcal infections-pharyngitis , scarlet fever , otitis media ,
mastoiditis ,subacute endocarditis
 Syphilis and gonorrhea
 Meningococcal infections
 Actinomycosis
 Anthrax
 Diphtheria
 Tetanus
 Gas-gangrene
 Rat-bite fever
 Prophylactic treatment of rheumatic fever and other infections mentioned
above. 14

15. ADVERSE EFFECTS
• Flushing
• Pruritus
• Hypotension
• Laryngeal edema
• Asthma
• Colic
• unconsciousness
Immediate
reactions
(anaphylaxis)
• Morbilliform eruptions
• Urticarial eruptions
• Pruritus
• Local inflammatory eruptions
Late reactions
• Immuno-hemolytic anaemia
• Drug fever
• Acute renal insufficiency
• thrombocytopenia
Unusual
reactions 15

16. Toxicity
 Usually free from toxic effects but deaths have
occurred due to anaphylaxis
 No toxic action on any organ or tissue of the body
 Allergic reactions are more common with
penicillin in oil of procaine penicillin
 These reactions are due to hypersensitivity or
altered reactivity of the patient
16

17. Penicillin reactions
1. Anaphylactic shock occurring within 1-6 minute after
inj. and at times fatal
2. Delayed reactions : occur after 15-20 minute and are
of a serious nature
3. Reactions at the site of injection after administration
of two or more injections at the same time. E.g.
exfoliative dermatitis
4. Agranulocytosis
 In allergic reactions and anaphylactic shock,
adrenaline, antihistaminics, corticosteroids and
calcium i.v. are drugs of choice.
17

18. Penicillin Sensitivity Test
 Carried out when pt. is receiving a dose of
penicillin for the first time.
 The pt. is injected slowly with 0.02 ml
(10,000units/ml)of penicillin intradermally and
site of inj. is watched for 15 min.
 There should not be a local reaction exceeding an
area of 10 mm or general reaction after the inj.
18

19. Repository Preparations of Penicillin-G
 Penicillin-G is rapidly excreted and the duration
of action is very short.
 Moreover, because of poor absorption and
destruction by gastric acid, it has to be given by
i.m. route.
 It is inconvenient to give injections 4 hourly
 To overcome this difficulty various repository
preparations are available
19

20. 1. Procaine benzylpenicillin:12-14 hrs duration of
action.
2. Fortified benzylpenicillin : procaine
benzylpenicillin combined with benzylpenicillin. Its
duration of action is 24 hrs.
3. Procaine penicillin in oil with 2% aluminium
monostearate (PAM): produces action for 72 hrs.
4. Benzathine penicillin: dibenzylethylene diamine
salt of benzyl penicillin having action for 2-3 weeks.
5. Penicillin with probenecid,PAHA or
carinamide : these agents prevent tubular secretion
of pcn and hence increase duration of action.
20

21. Disadvantages of Penicillin-G
 Inactivated by gastric acid
 Rapidly excreted
 Shorter duration of action
 Inactivated by penicillinase enzyme and so
resistance develops quickly(particularly with
staphylococci)
 Poor distribution to brain
 Narrow anti-bacterial spectrum
 Anaphylaxis is common
o These disadvantages made it essential to have
certain semi-synthetic penicillins.
21

22. SEMI-SYNTHETIC PENICILLINS
1. Acid resistant penicillins (Oral penicillins):
o penicillin V
o Phenethicillin
o Propacillin
2. Penicillinase resistant penicillins:
o Methicillin
o Cloxacillin
o Oxacillin
o Dicloxacillin
o quinacillin
22

23. 3. Extended spectrum penicillin:
a) Amino penicillins: ampicillin , amoxicillin ,
pivampicillin , bacampicillin , talampicillin
b) Carboxy penicillins: carbenicillin , ticarcillin
c) Ureidopenicillins: piperacillin , azlocillin
4. Reversed spectrum penicillins:
o Mecillinam
o Pivmecillinam
o Temocillin
23

24. 1. Acid resistant Penicillins
 Less effective as compared to benzyl penicillin
but they can be given orally.
 Sensitive to penicillinase enzyme.
 Anti bacterial spectrum is similar to that of
benzyl penicillin.
 Used in less serious infections of pneumococci and
streptococci.
 E.g. Penicillin-V, Phenethicillin, Propacillin.
24

25. 2. Penicillinase resistant Penicillins
 They are also acid resistant (except methicillin).
 Methicillin is less effective than penicillin-G. It is
however, used in staphylococal infections.
 Cloxacillin is 5-10 times more potent than
methicillin. It may, however, produce allergic
reactions.
 Mainly useful in staphylococcal infections.
25

26. 3. Extended spectrum Penicillins
• All broad spectrum penicillins are sensitive to enzyme
penicillinase.
Ampicillin
 semi-synthetic antibiotic derived from 6-APA.
 Antimicrobial spectrum:
1. Gram +ve: Streptococcus faecalis, S. pneumoniae
and Haemolytic streptococci
2. Gram –ve: E. coli,H. influenza, Salmonella and
Shigella
3. Listeria monocytogenes – highly sensitive
 MIC is 0.02-6 mcg/ml
26

27.  Stable in gastric secretion and is well absorbed
from GI tract after oral administration.
 Food interferes with the absorption.
 Peak concentrations in the serum are obtained in
about 1-2 hrs and are reported to range from
0.8-8.5 mcg/ml
 Anhydrous ampicillin produce earlier and higher
serum levels.
27
Absorption and Fate:

28. Therapeutic Uses :
1. Respiratory tract infections : pneumonia, acute
and chronic bronchitis
2. Urinary tract infections : cystitis and other lower
infections, acute or chronic pyelonephriris,
gonorrhea; non specific urethritis
3. Typhoid and paratyphoid
4. Shigella infections
28

29. Amoxicillin
 It is d-8-amino-p-hydroxybenzyl penicillin.
 Resistant towards gastric acid but sensitive to
penicillinase.
 The absorption and penetration of amoxicillin is better
into certain body tissues and fluids as compared to
ampicillin.
 Food doesn’t interfere with absorption.
 Peak plasma concentration are achieved upto twice as
high as that from the same dose of ampicillin
 Effective against same range of microbes as
ampicillin, except shigellosis (less effective) 29

30. Therapeutic Uses
1. In haemolytic streptococcal, staphylococcal,
meningococcal, gonococcal,Treponema pallidium
and Pneumococcal infections, it is very effective.
2. As prophylactic against pyogenic complications of
viral diseases.
3. In major surgeries , for preparation of the field of
operation.
30

31. Pivampicillin
 Converted into ampicillin in the body and higher
ampicillin serum level is achieved as compared to
ampicillin alone.
 However, poorly absorbed on oral administration
Talampicillin
 It is also metabolized into ampicillin in the body
and highest level of the latter can be achieved in
the blood and thus bacterial resistance can be
minimized.
31

32. Bacampicillin
 1-ethoxycarbonyl oxyethyl ester of ampicillin
 Absorbed well after oral administration and is
hydrolyzed to ampicillin.
 Blood concentrations are 50% higher than those
achieved with amoxicillin.
 Effective when given twice a day.
32

33. Carbenicillin
 Penicillinase susceptible derivative of 6-APA.
 Major advantage of this agent is that it often
cures serious infections caused by Pseudomonas
and Proteus strains resistant to ampicillin.
 Gram –ve micro organisms like E. coli ,
Enterobacter and Salmonella are less sensitive.
 Klebsiella and Serratia are resistant.
 It is not absorbed from GIT and hence must be
given by parenteral route (IM route)
33

34.  It may cause adverse effects reported for
penicillin.
 In addition, congestive cardiac failure may result
from the administration of excessive Na+(as
carbenicillin is marketed as disodium salt).
 Ticarcillin, azlocillin and piperacillin are similar
to carbenicillin but give higher blood levels and
are effective against gram negative aerobes.
 They are, however, poorly absorbed from oral
route.
34

35. 4. Reversed spectrum penicillins
 Mecilllinam :
 Not effective against Gram +ve cocci but highly
active against Gram –ve bacilli like E.coli,
Salmonella, Klebsiella and Enterobacter.
 Not active against Pseudomonas
 Used in typhoid, dysentery and UTIs.
 Pivmecillinam is prodrug converted to
mecillinam.
35

36. Resistance to penicillins
 Resistance to penicillins may develop due to
following reasons:
1. Decreased affinity between antibiotics and
the target PBPs. E.g. streptococcal species
36

37. 2. Decreased ability
to permeate the
outer membrane
of the bacteria,
thus reducing its
ability to gain
access to the
PBPs, which are
on the inner side
of the membrane
(E.g. Gram –ve
bacteria).
37

38. 3. Production of beta-lactamases(penicillinase)
which destroy beta-lactam antibiotic before they
can interact with PBPs. E.g., S.aureus, E.coli,
Enterobecter spp, Haemophilus spp
38

39. 39

40. Beta-lactamase Inhibitors
 They bind with beta-lactamase enzyme and inactive
them.
 Hence, they prevent destruction of beta-lactam
antibiotics.
 Clavulinic acid, sulbactam and tazobactam are the
examples
1. Clavulinic acid:
 Inhibits penicillinase
 Obtained from Streotomyces clavuligerus
 It is beta-lactam compound but devoid of antibacterial
activity.
40

41.  Enhances the activity of a number of beta-lactam
antibiotics against organisms like S.aureus,
H.influenza, N.gonorrhoea, E.coli, Shigella and
Salmonella.
 It is, however, not effective against penicillinase
produced by Pseudomonas aeruginosa, Serratia
marescen, Citrobact sp., Enterobacter and Proteus.
 Well absorbed orally.
 P’kinetic parameters matches with amoxicillin so it
is combined with amoxicillin.
 Combined with ticarcillin also.
41

42. 2. Sulbactam:
 Semi-synthetic beta-lactamase inhibitor .
 Resembles chemically as well as in activity to
clavulanic acid.
 Can be given orally or parenterally in combination
with ampicillin.
3. Tazobactam:
 similar to sulbactam and combined with
piperacillin.
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43. Any Questions ?
43

44. Thank You
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