UNIT # 04

CHAPTER # 01 PENCILLINS

PENICILLINS

INTRODUCTION:

The Penicillins constitute one of the most important groups of antibiotics. Although
numerous other antimicrobial agents have been produced since the first penicillin became
available, these still are used widely, and major antibiotics and new derivatives of the basic
penicillin nucleus still are being produced. Many of these have unique advantages such that
members of this group of antibiotics are currently the drugs of choice for a large number of
infectious diseases.

History:

The history of the brilliant research that led to the discovery and development of penicillin
is well chronicled. In 1928, while studying Staphylococcus variants in the laboratory at St.
Mary's Hospital in London, Alexander Fleming observed
that a mold contaminating one of his cultures caused the
bacteria in its vicinity to undergo lysis. Broth in which the
fungus was grown was markedly inhibitory for many
microorganisms. Because the mold belonged to the genus
Penicillium, Fleming named the antibacterial substance
penicillin.A decade later, penicillin was developed as a systemic therapeutic agent by the
concerted research of a group of investigators at Oxford University headed by Florey, Chain,
and Abraham. By May 1940, the crude material then available was found to produce
dramatic therapeutic effects when administered parenterally to mice with experimentally
produced streptococcal infections. Despite great obstacles to its laboratory production,
enough penicillin was accumulated by 1941 to conduct therapeutic trials in several patients
desperately ill with staphylococcal and streptococcal infections refractory to all other
therapy.

CLSSIFICATION OF THE PENICILLINS:

It is classified on different basis, these are given as under;

A). According to the nature:

1). Natural penicillins:
e.g. Pencillin G or benzyl penicillin.
2). Semi-synthetic penicillines:
 Long acting Penicillines: e.g. procaine penicillin, benzathine penicillin G.
 Orally effective Penicillines: e.g. Phenoxymethyl penicillin ( Penicillin V),
phenbenicillin, Propicillin.
 Penicillinase Resistant Penicillins: e.g. Methicillin, Nafcillin, Oxacillin, Cloxacillin,
Dicloxacillin, Flucloxacillin.
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 Broadspectrum penicillins: e.g. Ampicillin, Amoxycillin, Bacampicillin,
Pivampicillin,Cyclacillin, Hetacillin, Amoxycillin plus Clavulanic acid, Ampicillin
plus Cloxacillin, Amdinocillin.
 Anti-pseudomonal Pencillins: e.g. Carbenicillin, Carbenicillin indanyl, Ticarcillin,
Azlocillin, Mezlocillin, Piperacillin.

B). According to pencillinase Sensitivity:

1) Penicillinase sensitive:
 Acid labile: e.g. Penicillin G, Procaine Pencillin, Benzathine Pencilline G,
Carbenicillin, Piperacillin, Amdinocillin.
 Acid Stable: e.g. Pencillin V, Phenbencillin, Propicillin, Ampicillin, amoxicillin,
Bacampicillin, Pivampicillin, Amoxycillin plus Clavulanic acid, Ampicillin plus
Cloxacillin, Carbenicillin indanyl.
2) Penicillin Resistant:
 Acid labile: e.g. Methicillin, Nafcillin.
 Acid Stable: e.g. Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin.

STRUCTURE:

All penicillins have the basic structure, in which a thiazolidine ring is attached to a -lactam
ring that carries a secondary amino group (RNH-). Substituents can be attached to the amino
group. Structural integrity of the 6-aminopenicillanic acid nucleus is essential for the
biologic activity of these compounds. Hydrolysis of the -lactam ring by bacterial -
lactamases yields penicilloic acid, which lacks antibacterial activity.

Structures of different Pencillins are given below.

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PHARMACODYNAMICS:
Mechanism of action:
Penicillins, like all -lactam antibiotics, inhibit bacterial growth by interfering with the
transpeptidation reaction of bacterial cell wall synthesis. The cell wall is a rigid outer layer
unique to bacterial species. It completely surrounds the cytoplasmic membrane maintains
cell shape and integrity, and prevents cell lysis from high osmotic pressure. The cell wall is
composed of a complex cross-linked polymer of polysaccharides and polypeptides,
peptidoglycan (murein, mucopeptide). The polysaccharide contains alternating amino
sugars, N-acetylglucosamine and N-acetylmuramic acid. A five-amino-acid peptide is linked
to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine.
Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of
forming a cross-link with a nearby peptide. Cross-links give the cell wall its structural
rigidity. -Lactam antibiotics, structural analogs of the natural D-Ala- D-Ala substrate,
covalently bind to the active site of PBPs.
The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or
cross-linkage1), resulting in exposure of the osmotically less stable membrane. Cell lysis can
then occur, either through osmotic pressure or through the activation of autolysins. These
drugs are thus bactericidal. The success of a penicillin antibiotic in causing cell death is
related to the antibiotic's size, charge, and hydrophobicity. Penicillins are only effective
against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently,

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they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa,
fungi, and viruses.

ANTI-BACTERIAL SPECTRUM:

The antibacterial spectrum of the various penicillins is determined, in part, by their ability to
cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space.
Factors that determine the susceptibility of PBPs to these antibiotics include the size, charge,
and hydrophobicity of the particular beta-lactam antibiotic. In general, gram-positive
microorganisms have cell walls that are easily traversed by penicillins and, therefore, in the
absence of resistance are susceptible to these drugs. Gram-negative microorganisms have an
outer lipopolysaccharide membrane (envelope) surrounding the cell wall that presents a
barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins
inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to
permit transmembrane entry. Pseudomonas aeruginosa lacks porins, making these organisms
intrinsically resistant to many antimicrobial agents.

FIGURE: The penicillinase-resistant penicillins are oxacillin, cloxacillin, dicloxacillin,

methicillin, and nafcillin. These agents are the drugs of choice for treating infections
caused by penicillinase-producing Staphylococcus aureus.

SYNTHESIS OF PENICILLINS:

The synthesis of different types of penicillins is;

 Benzylpenicillin: It is the gold standard penicillin, which is obtained

biotechnogically using the fungus P. chrysogenum as the producer, and phenylacetic
acid as the precursor.

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 Phenoxymethylpenicillin: Phenoxymethylpenicillin is also obtained
biotechnologically using the fungus P. chrysogenum as the producer and
phenoxyacetic acid as the precursor.
 Methicillin: Methicillin is synthesized by acylating 6- APA with 2, 6-
dimethoxybenzoic acid chloride in the presence of triethylamine.

Figure showing synthesis of Methicillin

 Oxacillin: Oxacillin is synthesized by reacting 5-methyl-3-phenyl-4-

isoxazolcarboxylicacid chloride with 6-APA in the presence of sodium bicarbonate.

Figure showing synthesis of Oxacillin

 Cloxacillin: 6-APA is duly acylated with 3-(o-chlorophenyl)-5-methyl-4-isoxazole

carboxylic acid and the resulting cloxacillin base is adequately purified by
recrystallization. The base thus obtained is converted to the corresponding sodium
salt by treating with an equimolar concentration of NaOH.

Figure showing synthesis of Cloxarcillin

 Ampicillin: A method of directly acylating 6-APA with phenylglycine chloride

hydrochloride has been proposed, That is given as under.

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Figure showing synthesis of Ticarcillin

 Ticarcillin: Ticarcillin is synthesized by direct acylation of 6-APA in the presence

of sodium hydroxide, but with 3-thienylmalonic acid chloride, which gives
ticarcillin.

Figure showing synthesis of Ticarcillin

STRUCTURAL ACTIVITY RELATIONSHIP:

The stereochemistry along the lactam ring is required of penicillin, as well as the carboxyl
group on the thiazolidine ring. The sulfur atom on this ring has been substituted in certain
studies, but is kept present for the molecule to be classified as penicillin. The acyl-amino
side chain is required, but the R-group can be varied.
Because the R-group is the only variable component of the molecule, the identity of a
penicillin molecule is dependent entirely upon the chemical make-up of R. Therefore, the
variation of the R-group is key in making semi-synthetic penicillin analogues. These
chemical analogues vary in their acid sensitivity, bacterial resistance, and efficacy against
certain types of bacteria.
Some of the synthetic analogues of pencillins are;

1. Oxacillin: Evidently, the steric effects due to the presence of inherent 3-phenyl and
5-methyl moieties of the isoxazolyl ring not only prevent the binding of this
penicillin to the β-lactamase active site but also afford protection to the ensuing
lactam ring from degradation. The ‘drug’ is found to be comparatively resistant to
acid hydrolysis and; hence, could be given orally with good pharmacologic effect.

2. Ampicillin. The D-(–) ampicillin is found to be more active appreciably in

comparison to its isomer L-(+) ampicillin. The α-amino function in ampicillin gets
protonated extensively in an acidic media that perhaps legitimately offers a
satisfactory explanation with respect to ampicillin’s stability to acid hydrolysis, and
observed instability to alkaline hydrolysis.

3. Methicillin. The steric hindrence afforded by the presence of 2, 6-dimelthoxy

moieties categorically renders the ‘drug’ resistant to enzymatic hydrolysis.

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4. Ticarcillin. The ‘drug’ happens to be an ‘isostere’ of carbenicillin wherein the
‘phenyl’ moiety has been duly replaced by a ‘thienyl’ group as shown below:

CLINICAL USES:

Except for oral amoxicillin, penicillins should be given 1-2 hours before or after a meal;
they should not be given with food to minimize binding to food proteins and acid
inactivation. Blood levels of all penicillins can be raised by simultaneous administration of
probenecid, 0.5 g (10 mg/kg in children) every 6 hours orally.

A). Pencillins:
1. Penicillin G: These are the natural pencillins It is a drug of choice for infections
caused by streptococci, meningococci, enterococci, penicillin-susceptible
pneumococci, non-beta-lactamase-producing staphylococci, Treponema pallidum
and many other spirochetes, clostridium species, actinomyces, and other gram-
positive rods and non- beta-lactamase-producing gram-negative anaerobic
organisms.
2. Penicillin V: The oral form of penicillin, is indicated only in minor infections
because of its poor bioavailability, the need for dosing QID, and its narrow
antibacterial spectrum.
3. Benzathine Penicillin And Procaine Penicillin G: It is for intramuscular injection
yield low but prolonged drug levels. A single intramuscular injection of benzathine
penicillin, 1.2 million units, is effective treatment for hemolytic streptococcal
pharyngitis; given intramuscularly once every 3-4 weeks, it prevents reinfection.
Benzathine penicillin G, 2.4 million units intramuscularly once a week for 1-3
weeks, is effective in the treatment of syphilis.

B). Penicillins resistant to staphylococcal beta-lactamase:

These semisynthetic penicillins are indicated for infection by beta-lactamase-producing
staphylococci, although penicillin-susceptible strains of streptococci and pneumococci are
also susceptible. Listeria, enterococci, and methicillin-resistant strains of staphylococci are
resistant.

C). Extended-spectrum penicillins:

These drugs have greater activity than penicillin against gram-negative bacteria because of
their enhanced ability to penetrate the gram-negative outer membrane.

 The amino-penicillins, ampicillin and amoxicillin, have identical spectrum and

activity, but amoxicillin is better absorbed orally. These drugs are given orally to
treat urinary tract infections, sinusitis, otitis, and lower respiratory tract infections.
Ampicillin and amoxicillin are the most active of the oral beta-lactam antibiotics
against penicillin-resistant pneumococci and are the preferred beta-lactam antibiotics

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for treating infections suspected to be caused by these resistant strains. Ampicillin
(but not amoxicillin) is effective for shigellosis. Its use to treat uncomplicated
salmonella gastroenteritis is controversial because it may prolong the carrier state.
 Carbenicillin, the very first antipseudomonal carboxypenicillin, is obsolete. A
derivative, carbenicillin indanyl sodium, can be given orally for urinary tract
infections. There are more active, better tolerated alternatives. A carboxypenicillin
with activity similar to that of carbenicillin is ticarcillin.
 The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are also active against
selected gram-negative bacilli, such as Klebsiella pneumoniae.

DOSAGE:

 Penicillin G ……………………………………….……. 0.6-5 million units/day; IM

QID.
 Penicillin V: Oral, adults and children over 12 years of age or older, usually 125 to
500 mg 3 to 4 times a day.
 Procain penicillin ………………………………………… 4.8 -10 million units, OD, IM.
 Ampicillin ………………………………………...… 300-500mg QID; Orally, IM or IV.
 Cloxacillin ……………………………………….…..... 0.25-0.5 orally every 4-6 hours.
 Carbencillin ………………………………………...……………… 300-500 mg/kg/d; IV.

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