Penicillin Facts

o     It is a β-Lactum antibiotic

o     It is a bactericidal

o     It inhibits bacterial cell wall synthesis

o     It is most widely used

o     It is remarkably safe drug

o     Mostly excreted unchanged in the urine

o     Can be given safely in pregnancy

Source / History—

In 1929, Alexander Flemming discovered Penicillin from Penicillium mold known as Penicillium notatum. It can also be produced from Penicillium chrysogenum.

Chemistry—

The nucleus is known as 6-Amino Penicillanic acid.

Penicillin consists of—

1.      Thiazolidine ring (5 membered sulphur containing ring)

2.      β-Lactum ring (4 membered nitrogen containing ring)

3.      Side chain with amide group.

So, nucleus of Penicillin is = Thiazolidine ring + β-Lactum ring + Side chain.

o     β-Lactum ring is responsible for the anti-bacterial activity of Penicillin.

o     Substitute in the R position is responsible for the—

a.      Acid stability of the stomach

b.      Spectrum

c.       Potency

o     β-Lactum ring can be cleaved by β-lactamase enzyme and producing penicilloic acid which is devoid of anti-bacterial activity. This side chain is cleaved by amidase enzyme and again producing 6-amino penicillanic acid which also has anti-bacterial activity.

Classification—

A.  Natural Penicillin /  Narrow spectrum—

a.      Penicillin-G (Benzyl Penicillin)—broad spectrum.

b.      Penicillin-M (Phenoxy-methyl Penicillin)

B. Anti-staphylococcal Penicillin / β-lactamase resistant Penicillin—

a.      Cloxacillin

b.      Flucloxacillin

c.       Dicloxaxillin

d.     Oxacillin

e.      Nafcillin

f.        Methicillin

C. Extended spectrum / Broad spectrum—

a.      Aminopenicillin—Ampicillin, Amoxicillin, Ampicillin prodrug (Bac-Ampicillin, Tal-Ampicillin, Pivampicillin)

b.      Amidino-Penicillin—Pivmecillinium, Mecillinium

c.       Carboxy Penicillin—Carbenecillin, Ticarcillin

d.     Ureido Penicillin—Azlocillin, Mezocillin, Piperacillin

 *** Carboxy-Penicillin and Ureido-Penicillin are collectively called Anti-Pseudomonal Penicillin

D. Long acting Penicillin—

a.      Procaine Penicillin (Penicillin-G added with Procaine salt)

b.      Benzathene Penicillin (Penicillin-G added with Benzathene salt)

*** both the drugs act as depot.

*** to each molecule of N-acetyl muramic acid a tetrapeptide is attached. Tetrapeptide consists of L-alanine, D-alanine, L-lysine & D-glutamic acid. Finally these polymer strands are cross linked by amino acid bridges of glysine which connects the L-lysine of one tetrapeptide to the D-alanine of another. This cross linking is known as “Transpeptidation Reaction” which is carried out by an enzyme Transpeptidase (Endopeptidase + Glycosidase).

Mechanism of Action—

1.  Penicillin enters through cell wall and binds with PBP (Penicillin binding protein) on cell wall of bacteria.

2.  It inhibits the transpeptidation reaction by inhibiting the enzyme transpeptidase. So it inhibits the synthesis of peptidoglycane layer and hampers the cross linkage formation. That’s why cell wall becomes weak.

3.  It activates the autolytic enzyme by inhibiting the inhibitors of autolysis thereby autolysis occurs.

—thus the cell wall becomes weak and breaks down.

Pharmacokinetics—

Absorption—

o     Most of the Penicillins are incompletely absorbed from GIT except Amoxicillin.

o     Penicillin-G is absorbed 30%.

o     Other Penicillin like Ampicillin and Cloxacillin are relatively acid stable and more absorbed (70-80%).

o     Food interferes with the absorption except Amoxicillin.

So, these drugs are given one hour before meal and two hours after meal.

Distribution—

·    Penicillin is widely distributed throughout the tissue including synovial, pericardial and pleural fluid.

·    It is bound to the plasma protein to different extents. (Benzyl Penicillin 60%, Nafcillin 90%)

·    It cannot enter inside the cell remains in the ECF.

·    It doesn’t cross the BBB

(but during meningitis it can be given due to ↑ vascular permeability, ↑ protein binding in CSF and ↓ efflux from CNS)

·    Serum half life is 30 min to 1 hr.

·    All Penicillins can cross the placental barrier but not teratogenic.

Metabolism—

Very poorly metabolized.

Excretion—

Most are excreted through urine. (90% by tubular secretion, 10% by glomerular filtration)

*** Probenecid blocks the tubular secretion of Penicillin.

To increase the serum concentration of Penicillin we use—

1.  Probenecid + Penicillin

2.  β-Lactamase inhibitor + Penicillin

β-lactamase inhibitors—

1.  Clavulanic acid

2.  Sulbactum

3.  Tazobactum

§   Potent inhibitors of β-lactamase

§   Protects hydrolysable penicillin

§   They can extend the spectrum of action of Penicillin

§   Available in fixed combination with specific Penicillin. Ex-Amoxiclav (Amoxicillin + Clavulanic acid)

§   Main indication of use is as emipirical therapy for wide range of infections

§   They themselves do not have anti-microbial activitybut act as inhibitors of the β-lactamase enzyme

Antimicrobial Spectrum / Clinical Uses of Penicillin (Penicillin-G)—

a.   Gram positive coccal infection—

1. Streptococcus pneumoniae—it causes Pneumonia, Meningitis, Arthritis, Osteomyelitis, Endocarditis, Pericarditis, Mastoiditis.
2. Group-A streptococcus—it causes streptococcal Pharyngitis, Scarlet Fever, Otitis.
3. Non β-Lactamase producing staphylococci.

b.  Gram negative cocci—Gonococcus, Meningococcus.

c.  Against enterococci.

d. Against syphilis—cause by Treponema pallidum.

e.  Most of the oral anaerobic organism.

f.  Cornybacterium diptheriae—Diphtheria

g.  Clostridium—causes tetanus, gas gangrene

h.  Bacillus anthracis—causes anthrax

i.   Listeria monocytogenes—Listeriasis (food poisoning)

j.   Actinomyces

Limitations of Penicillin-G—

§  Unstable in gastric pH, there fore not give orally

§  Susceptible to destruction by β-lactamase

§  Relatively inactive against gm –ve bacteria

§  Narrow spectrum of action, short duration of action

Penicillin-V

Penicillin-V is indicated only for mild or moderate group-A streptococcal infections—

a.  Streptococcal pharyngitis

b.  Scarlet fever

c.  Otitis media

Criteria of Penicillin-V—

o     It is less absorbed

o     Bioavailability is less

o     Frequent dosing interval

o     Narrow microbial spectrum

Anti-staphylococcal Penicillin

o     It is also called Semisynthetic or β-lactamase Resistant Penicillin.

o     Sole indicator is β-lactamase producing Antistaphylococcal Penicillin.

Criteria—

o     Well absorbed

o     Can be given orally

o     Relatively acid stable

o     Resistant to β-lactamase

Extended spectrum / Broad spectrum—

o     Example—Ampicillin, Amoxicillin

o     More effective than Penicillin-G. (Penicillin-G + more effective against gm –ve bacilli and enterococci)

Uses—

o     In Listeria infection

o     Prophylaxis of bacterial endocarditis during surgery, mainly dental extraction.

o     Some form of Gonorrhea.

o     Against Haemophillus influenzae that causes Sinusitis, Otitis media, Meningitis.

o     E. coli or Proteus mirabilis causing UTI.

o     Salmonella infection such as typhoid.

Prophylactic use of Penicillin-G and Penicillin-V—

a.  Streptococcal infection (recurrent)

b. Rheumatic fever (recurrent)

c.  Opthalmia gonococcal neonatorum

d. Patient having valvular disease undergoing surgery—dental extraction, tonsillectomy, genito-urinary operation.

Anti-Pseudomonal Penicillin

Amidinopenicillin—Pivemecillin, Mecillinium.

It is extremely active against gm –ve bacteria. It is used against enterobacteria, to eradicate salmonella carrier.

It has poor activity against gram –ve cocci.

Benzathene Penicillin

1 vial contains 1.2 million units.

Therapeutic uses—

·    In β-Haemolytic streptococcal pharyngitis—single dose 1.2 million units (IM)

·    In Syphilis—2.4 million units IM once a week for 3-4 weeks.

Prophylactic uses—

·    Satisfactory prophylaxis against re-infection with β-haemolytic streptococci. 1.2 million once every 3-4 weeks.

·    Rheumatic fever—1.2 million units every 3-4 weeks.

Ureido Penicillin—

These are the Penicillin obtained from the Ampicillin containing the side chains of Urea. Ex—Piperacillin

These drugs are given parenterally and are available as Na-salts

They are highly efficacious against pseudomonas species

Eliminated through the urine

Monobactums—Aztreconamus

§  They have monocyclic ring structure

§  Relatively resistant to β-lactamase

§  They have good activity against pseudomonas species

§  No activity against anaerobes

Adverse effects of Penicillin—

Allergic—

§  Drug fever, rash

§  Anaphylactic shock

§  Interstitial nephritis

§  Hepatitis

Non-allergic—

§  Opportunistic infection (Superinfection)

§  Haemolytic anaemia

§  Diarrhoea (drugs which are less absorbed cause diarrhoea)

§  Neurotoxicity

§  Local tissue injury (induration, Thrombophlebitis, accidental nerve injury)

Hypersensitivity—

o     All the Penicillins are non-toxic drugs. Most of the serious effects are due to hypersensitivity reaction.

o     All the Penicillins are cross sensitizing and cross reacting.

o     This hypersensitivity reaction is not dose dependent, it may occur even in one dose.

o     The major antigenic determinant is Penicilloic acid and hydrolytic alkaline product. This alkaline product combines with the body protein and produces Hapten and then produces immune reaction.

o     The hypersensitivity reaction can cause mild rash to anaphylaxis.

Anaphylactic reaction—

o     It is type-1 hypersensitivity reaction

o     It is IgE mediated

o     It is not dose related

o     Very severe type of reaction but incidence is very rare (0.05%)

Mechanism of Action—

When Penicillin enters the body, the body produce IgE mediated antibody and attaches it on the cell membrane of the mast cell. During 2^nd exposure the antigen comes to the mast cell and antigen antibody reaction takes place and there is degranulation of the mast cell. Large amount of histamine is released along with heparin and other chemical mediators. Due to more histamine—

§  Vasodilatation occurs and the patient develops shock.

§  Severe asthma develops due to bronchoconstriction.

Clinical features—

1.   Onset is most dramatic

2.   Very severe hypotension

3.   Shock

4.   Severe bronchoconstriction and asthma

5.   Abdominal pain

6.   Purpuric skin lesion

7.   Nausea

8.   Vomiting

9.   Extreme weakness

Drug of choice—

1.   Adrenalin

2.   Corticosteroid

3.   Anti-histamine

4.   Maintenance of the fluid and electrolyte balance

Differences between Amoxicillin and Ampicillin—

Traits	Amoxicillin	Ampicillin
Lipid solubility	More	Less
Absorption in GIT	More	Less
Bioavailability	Higher	Lower
Half life	8 hours	6 hours
Duration of action	More	Less
Effect of food on absorption	Food effects absorption	Not so
Route	Mainly oral	Oral and parenteral
Adverse effects	Less	More

Drugs with their routes of administration—

Drug	Routes of Administration
Benzyl Penicillin	IV, IM (very painful as IM)
Ampicillin	Oral, Parenteral
Amoxicillin	Oral
Penicillin-V	Oral
Procaine Penicillin Benzathene Penicillin	Oral (always)