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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5648_Библиотеки_им_академика_М_И_Перельмана.pdf
82 Pharmaceutical Chemistry
3.10.3 Mode of Action
NSAIDs affect renal and cardiovascular systems and the most common side effect is related
to gastrointestinal tract (GIT). The pharmacological activity of NSAIDs is related to their
ability to inhibit the activity of the enzyme COXs involved in the biosynthesis of PGH2. It
is now well known that COX exists in two isoforms, namely, COX-1 and COX-2, which are
regulated differently. COX-I is constitutively expressed in the stomach to provide
cytoprotection in the GIT. COX-II is inducible and plays a major role in prostaglandin
biosynthesis in inflammatory cells. Since, most of the NSAIDs used clinically inhibit both
isoforms, long- term use of these agents results in gastric ulcer and there is enough evidence
that inhibition of COX-I rather than that of COX-II underlies gastric ulcer formation. As a
result, a number of selective COX-II inhibitors, including celecoxib and rofecoxib have
been introduced for clinical use with exceptional anti-inflammatory properties and reduced
gastric toxicity. But initial enthusiasm for selective COX-II inhibitors as safer NSAIDs has
faded due to emergence of serious cardiovascular side-effects on long-term use. Thus, we
can say the traditional NSAIDs act by blocking the effects of the two COX (COX-1 and
COX-2) enzymes resulting in a reduced production of substances called prostaglandins.
Since some prostaglandins are involved in causing pain and inflammation at sites of injury
or damage in the body, a reduced production of prostaglandins reduces pain and
inflammation.
3.10.4 Metabolism of Diclofenac
Diclofenac is rapidly and completely (~100%) absorbed on oral administration with peak
plasma level being reached within 1.5-2.5 hours. The free acid (pK
= 4.0) is highly bound
a
to serum proteins (99.5%), primarily albumin. Only 50-60% of an oral dose is bioavailable
because of extensive hepatic metabolism. Four major metabolites resulting from aromatic
hydroxylation have been identified. The major metabolite via CYP3A4 is the 4-hydroxy
derivative and accounts for 20-30% of the dose excreted whereas the 5-hydroxy, 3-hydroxy,
and 4,5-dihydroxy metabolites via CYP2C9 accounts for 10-20% of the excreted dose (Fig.
3.11). The remaining drug is excreted in the form of sulphate conjugates. Although the
major metabolite is much less active than the parent compound, it can exhibit significant
biological activity, because it accounts for 30-40% all the metabolic products. Diclofenac
also has been reported to produce reactive benzoquinone-imine intermediates similar to
that reported in the metabolism of acetaminophen. These reactive intermediates are also
normally inactivated via conjugation with glutathione.
3.10.5 Side Effects of Diclofenac
Signs of an allergic reaction to diclofenac like hives, difficulty in breathing, swelling (in
face, lips, tongue, or throat), severe nausea, sudden or severe stomach pain, bloody or tarry
stools, coughing up blood or vomit that looks like coffee grounds, flu symptoms, pale skin,
unusual tiredness, swelling, rapid weight gain, worsening asthma (wheezing, chest
HO
Analgesics, Antipyretic and Anti-Inflammatory Agents 83
OH
Cl
Cl
Cl
NH
Cl
4-Hydroxy diclofenac Diclofenac
OH
O
Fig. 3.11: Metabolism of diclofenac
NH
Cl OH
Cl
NH
Cl
OH
5-Hydroxy diclofenac
O
HO
OH
O
4,5-Dihydroxy diclofenac
NH
Cl
O
3-Hydroxy diclofenac
Cl
NH
Cl OH
O
OH
OH
tightness, troubled breathing), heart attack symptoms like chest pain or pressure, pain
spreading to your jaw or shoulder, nausea, sweating; signs of a stroke like sudden
numbness or weakness (especially on one side of the body), sudden severe headache,
slurred speech, problems with vision or balance, liver problems like upper stomach pain,
itching, feeling tired, loss of appetite, dark urine, clay-like coloured stools, jaundice
(yellowing of the skin or eyes), signs of a kidney problem like little or no urination, painful
or difficult urination, swelling in feet or ankles or severe skin reaction like fever, sore
throat, swelling in face or tongue, burning in eyes, skin pain, followed by a red or purple
skin rash that spreads (especially in the face or upper body) and causes blistering and
peeling. Older adults may be more likely to have serious stomach problems while taking
medicine that contains an NSAID.
QUESTIONS
1. What are antipyretics?
2. How do antipyretics act on human host?
3. What are analgesic drugs?
4. How do analgesics act on the human host?
5. What are pain-killers and how do they work?
6. What are anti-inflammatory agents?
7. What are non-steroidal anti-inflammatory drugs (NSAID)?
8. What is the difference between analgesic, antipyretic and anti-inflammatory drugs?
9. What are morphine and codeine and how do they get metabolized?
84 Pharmaceutical Chemistry
10. Are aspirin, ibuprofen and diclofenac non-steroidal anti-inflammatory drugs?
11. What is the synthesis of aspirin?
12. How does aspirin work in human host?
13. How does aspirin get metabolized in human host?
14. What is the synthesis of ibuprofen?
15. What is the green synthesis of ibuprofen?
16. How does ibuprofen work and get metabolized in human host?
17. What is the synthesis of paracetamol?
18. How does paracetamol work and get metabolized in human host?
19. Is paracetamol a non-steroidal anti-inflammatory drug?
20. What is the synthesis of diclofenac?
21. How is diclofenac metabolized? Explain the mode of action in human host.
4
Antibiotic, Antibacterial and
Antifungal Agents
4.1 INTRODUCTION
Antibiotics are a class of medicines (chemical moieties) that are used to treat or kill infection
caused by pathogenic microbes, i.e., bacteria/germs/fungus. They are basically produced
by microorganisms in the form of natural and semi-synthetic products and are able to
inhibit the growth of the simple microorganisms, bacteria and pathogenic microbes. Semisynthetic antibiotics are generally chemically modified versions of natural antibiotics.
Thus, the action of particular antibiotics leads to distinction among the various antimicrobial
drugs produced by microorganisms or semi-synthetically synthesized.
The basic concept behind the antimicrobial action is a selective toxicity against the
growth of the infectious microorganism by certain drugs without harming the host cells.
Antimicrobial drugs specially used in the clinical practices are selectively toxic with respect
to microorganisms. The antibacterial effect of all the antimicrobial drugs can be executed
by using one or all of the following mechanisms:
Inhibition of cell membrane synthesis in microorganisms (viz., cycloserine,
vancomycin, and E-lactam antibiotics, etc.).
Inhibition of protein synthesis in microorganisms (viz., tetracyclines, erythromycin,
chloramphenicol, aminoglycosides, clindamycin, etc.).
Inhibition of nucleic synthesis function in microorganisms (viz., rifampicin,
quinolones, sulfonamides, metronidazole, trimethoprim, etc.).
External or cytoplasmic membrane inhibition (or alteration) of microorganisms (viz.,
polymixin).
H
R
N
O
O
Penicillins Cephalosporins Carbapenems Monobactams
S
CH
3
N
CH
COOH
3
H
R
N
O
O
N
S
COOH
R
1
OH
H3C
O O SO
S
N
COOH
SR
R
O
1
H
N
N
H
3
86 Pharmaceutical Chemistry
Alexander Fleming discovered penicillin in 1929, a substance produced by fungi that
seemed to inhibit bacterial growth and later its human trials were studied (E. Chain & H.
Florey). Antibiotics are widely used in pneumonia and other bacterial infections while less
studies are available for diagnosed viral infections (viz., cold and flu). It is mandatory to
take full course of antibiotics after doctor’s prescription.
Antibiotics are classified based on their mechanism of action. Each antibiotic has
different mechanism of action and acts against specific bacterial and parasitic infections.
Thus, different types of antibiotic drugs are used to treat different types of infections. The
commonly known antibiotics are penicillins (viz., amoxicillin, phenoxymethylpenicillin
and flucloxacillin, etc.), tetracyclines (viz., tetracycline, lymecycline and doxycycline, etc.),
sulfonamides and trimethoprim (viz., cotrimoxazole), cephalosporins (viz., cefalexin, cefaclor,
and cefadroxil, etc.), macrolides (viz., chloramphenicol, erythromycin, azithromycin and
clarithromycin, etc.), clindamycin, metronidazole and tinidazole, amino-glycosides (viz.,
gentamicin and tobramycin) and quinolones (viz., norfloxacin, ciprofloxacin, and
levofloxacin, etc.).
Antimicrobial drugs can be classified on the basis of their mode of action as bacteriostatic
(viz., sulfonamides and tetracyclines) and as bactericidal (viz., penicillin). Bacteriostatic
drugs do not destroy the microorganisms but inhibit the bacterial growth. It can be
anticipated that the minimal bactericidal concentration (MBC) of such drugs will be
significantly higher than the minimal inhibitory concentration (MIC). Thus, using
bacteriostatic drugs finally allowed boosting neutrophils and other protective factors/
functions of the body which further helps to remove the pathogens.
Excessive or prolonged use of antimicrobial drugs can resist bacteria and be characterized
as internal resistance (genetics of microorganism which is coded in the chromosomes and
spread resistance to all progenies of the given type of microorganisms) or acquired
resistance (the given generation of a type of bacteria acquired the ability to counter the
administered antimicrobial drug). Acquired resistance led to change in the bacterial DNA
which finally generated new characteristic features in bacteria.
Both the resistances have identical biochemical mechanisms which can be explained by
any of the following reasons:
Bacteria generate some barriers, thus drugs cannot reach the binding site.
Bacterial enzymes inactivate or modify the drugs.
Bacteria can change their complexity which the drug cannot bind properly.
Altered metabolic pathways also don’t permit the drug to produce the desired effect.
Sometimes antibacterial drugs can have an additive effect, antagonism or synergism,
when the infectious microorganisms are exposed to two antimicrobial drugs. Thus, in
conclusion, antibiotics can also be classified according to their principal biological origin
(viz., certain microorganisms produce antibiotics), biological mechanism (viz., antibiotics
used to inhibit nucleic acids synthesis), biological spectrum (viz., narrow spectrum
antibiotics used mainly for Gram-positive organisms while broad spectrum antibiotics are
Antibiotic, Antibacterial and Antifungal Agents 87
used as antibiotics, antitumour, antifungal, antiamebic, and antituberculosis), and chemical
structure based (viz., tetracyclines, aminoglycosides, macrolids and E-lactam antibiotics, etc).
4.1.1 Side Effects
Numerous side effects have been reported with the different antibiotics while most
antibiotics do not demonstrate serious side effects. Common side effects include mild
stomach upset (nausea), liver dysfunction, diarrhoea, and soft stools (faeces), etc. A few of
the patients may have an allergic reaction to particular antibiotics which may have severe
to fatal allergic reactions. Antibiotics can kill off normal defence (good) bacteria which
inhibit in the bowel motion, vegina & vaginal and other parts of human body. Some other
side effects, viz., severe watery diarrhoea, abdominal cramps, breathing problem, vomiting,
hives, rashes, swelling (face, lips and tongue) and fainting (allergic reaction), vegina &
veginal itching or discharge, oral thrush (white patches on the tongue). Some antibiotics
may interact with other medicines that patient might be consuming concurrently.
4.2 ANTIBACTERIAL AGENTS
Derived from Greek, antimicrobial is, anti
(against), mikros (little) and bios (life). All the
drug agents who are active against microbial
organisms are called antimicrobial drugs. First
time, Anton van Leeuwenhoek (1670’s) observed
that bacteria are single-cell microorganisms by
using the microscope. However, the link with
the disease was not appreciated until French
scientist Louis Pasteur (1862) demonstrated that
specific bacterial strains were crucial to
fermentation.
During the later half of the 19
th
century, Koch
et al., were able to identify the microorganisms
Antibiotics vs Antimicrobials
An antibiotic is a low molecular
substance produced by a microorganism
that at a low concentration inhibits or
kills other microorganisms.
An antimicrobial is any substance of
natural, semi-synthetic or synthetic
origin that kills or inhibits the growth
of microorganisms but causes very less
or no damage to the host.
All antibiotics are antimicrobials, but
not all antimicrobials are antibiotics.
responsible for diseases such as tuberculosis,
cholera, and typhoid. Later on, Paul Ehrlich was credited with the concept of selectivity
who reported the existence of molecules that would bind to microbes, but not to host cells.
By 1910, Ehrlich had successfully developed the first example of a purely synthetic
antimicrobial drug known as salvarsan (arsenic-containing compound). Although, it was
not effective against a wide range of bacterial infections yet it was effective against the
protozoal disease, sleeping sickness (trypanosomiasis) and the spirochete disease of
syphilis. This drug was used until 1945 when it was replaced by penicillin (1928) and
proflavin (1934). Proflavin was effective against bacterial infections in deep surface wounds
and was used on greater scale during the World War II. It targets bacterial DNA rather
than protein. Despite the success story of this drug, it was not effective against bacterial
infections in the bloodstream. In 1935, the discovery of a red dye called “prontosil” was
effective against Streptococci infections in vivo. It is a prodrug for a new class of antibacterial
88 Pharmaceutical Chemistry
agents known as the sulfa drugs or sulfonamides. They were effective against bacterial
infections carried in the bloodstream.
After World War II, the effort continued to find other novel antibiotic probes, viz.,
peptide antibiotics (bacitracin (1945), chloramphenicol (1947), tetracycline antibiotics
(chlortetracycline (1948)), macrolide antibiotics (erythromycin (1952)), cyclic peptide
antibiotics (cycloserine (1955)), E-lactam antibiotics and cephalosporin (1955).
HO
H2N
As As
Salvarsan Prontosil Prolavine
NH
2
OH N NH2N SO
NH
4.2.1 Mechanisms of Antibacterial Action
Nuclear material
DNA
/RNA
Cytoplasm
(slime layer)
Fig. 4.1: The bacterial cell
Rifamycins
2
NH
2
2
Cell wall
Plasma membrane
RibosomesCapsule
Cell wall
NH2N NH
Flagellum
2
Sulfonamides
Cytoplasm
Polymyxins
Chloramphenicol
Streptomycin
Tetracyclines
Fig. 4.2: Sites of antibacterial actions
Penicillins
Cephalosporins
Cycloserine
Ribosomes
Antibiotic, Antibacterial and Antifungal Agents 89
Antibacterial agents can act on bacterial cells (Figs. 4.1 & 4.2), in the following ways:
Inhibition of cell metabolism: Antibacterial agents which inhibit cell metabolism
are called antimetabolites. These compounds selectively inhibit the metabolism of a
microorganism-causing infection. They perform it by inhibiting an enzyme-catalysed
reaction which is present in the bacterial cell only; however, absent in the host cell.
Example: sulfonamides.
Rupturing of bacterial cell wall: Rupturing of cell wall leads to bacterial cell lysis
(bursting), i.e., cell death. Example: Penicillins and Cephalosporins. Animal cells are
unaffected by those agents because these cells do not have a cell wall.
Interactions with the plasma membrane: Some antibacterial agents can affect
membrane permeability by interacting with the plasma membrane of the bacterial
cells. Example: tyrothricin and polymyxins.
Disruption of protein synthesis: Protein synthesis inhibition or disruption means
the particular essential enzymes cannot be synthesized that are required for the cell’s
survival. Example: tetracyclines, chloramphenicol, rifamycins and aminoglycosides
(viz., streptomycin).
Inhibition of nucleic acid transcription and replication: Nucleic acid function
inhibition prevents cell division and/or the synthesis of essential enzymes. Example:
nalidixic acid and proflavin.
Adverse effects of antibacterial drugs could be allergic reactions, headaches, vomiting,
hives, rashes, cardiac arrest, breathing difficulty, fever, arthritis, and sometimes damage
to vital internal organs also.
4.2.2 Common Antibacterial Drugs
There are many antibacterial agents in a variety of brand names. For example, popular
drugs like ampicillin or amoxicillin, penicillin, erythromycin, tetracycline, and
cephalosporin (keflex), etc. (Fig. 4.3).
4.3 ANTIFUNGAL AGENTS
Infectious diseases, oftenly chronic in nature which are caused by fungi are called mycoses.
Some mycotic infections are superficial and others are systematic infections. The fungal
infection grows very slowly in tissues thus very poor penetration of antimicrobial agents
is observed as compared to bacterial infections. Therefore, the treatment of fungal infections
usually requires prolonged treatment.
The fungal cell membrane contains ergosterol rather than the cholesterol found in
mammalian membranes. Yeasts, mushrooms, molds and rusts are the common examples
of fungal kingdom. Generally, fungi are involved in many biodegradation processes. Few
fungi can cause opportunistic infections if they interact directly to the skin wounds and on
inhalation lung and nasal problems can arise. Superficial infections can also arise into the
90 Pharmaceutical Chemistry
skin in the Microsporum, Trichophyton or Epidermophyton genera through dermatophytes.
The dermophytic infections are specially named on the basis of site of infection rather than
the causative organism (Table 4.1).
OH
O2N
HN
Chloramphenicol
OH
OOH
OH
OH
Me
Tetracyclin
HO
Me
MeO
AcO
Me
Me
OH
O
O
Me
O
R = H ( )Rifamycin B
COOH ( )Rifamycin SV
R = CH
2
OH
OH
O
O
NMe
MeMe
OH
O
Cl
O
R
Cl
CONH
OH
2
NH
Me
2
HOOC
Me
HO
O
Me
HO
Et
O
Me
N
O
Nalidixic acid
Me
OH
Me
O
O
Me
Erythromycin
Me
N
MH
2
H
N
O
O
OH
HO
O
O
NMe
Me
OMe
O
Me
2
Me
OH
Me
H2N NH
N
Proavin
S
Me
Me
N
COOH
Amoxicillin
Fig. 4.3: Common antibacterial drugs
HO
HO
OH
MeHN
HOOC
NOC
H
2
O
HN O
2
O
O
OHC
Streptomycin
NH
OH
N
H
O
N
HO
O
O
Me
H
N
O
O
OH
NH
O
HN
HN O
H
N
O
Tyrothricin
OH
OH
N
NH
NH
2
NH
2
O
NH
2
NH
N
2
2
Table 4.1: Dermophytic infections and their causative organisms
Dermophytic infection Causative organism
Tinea corporis (ring worm) Microsporum canis, Trichophyton mentagrophytes
Tinea pedis (athlete’s foot) T. mentagrophytes, T. rubrum, Epidermophyton floccosum
Tinea cruis (jock itch) T. mentagrophytes, T. rubrum, E. floccosum
Tinea capis (scalp) M. canis, T. tonsurans
Tinea barbae (beard/hair) T. mentagrophytes, T. rubrum
Tinea unguium (nails) T. mentagrophytes, T. rubrum, E. floccosum
Systemic infections result in fungal pneumonia by the inhalation of spores. Systematic
fungal infection also arises due to the many organisms confined to specific geographic
locations, which affect the whole body, rather than individual parts or organs (Table. 4.2).
Antibiotic, Antibacterial and Antifungal Agents 91
Table 4.2: Systemic infections, causative organisms and their geographic location
Systemic infections Causative organism Geographic location
Coccidioidomycosis Cocidioides immitis Southwestern U.S. and parts of Latin America
Histoplasmosis Histoplasma capsulatum Central and Eastern U.S.
Brazilian Blastomycosis Paracoccidioides brasiliensis South America
Blastomycosis Blastomyces dermatitidis Southeastern U.S. & Mississippi River valley
Some organisms are affected by opportunistic infections which finally cause serious or
sometimes life-threatening infections (viz., cancer, diabetes, leukemia, blood diseases, HIV
and various immunodeficiency infections) (Table 4.3).
Table 4.3: Opportunistic infections, causative organisms and their target organs
Opportunistic Infections Causative Organism Target Organs
Candidaisis, Thrush,
Vulvovaginitis
Cryptococcal meningitis Cryptococcus neoformans Through inhalation, may cause mild lung
Aspergillosis Aspergillus sp. Lung, brain, sinuses and other organs
Mucormycosis Murcor sp. Sinuses, eyes, blood and brain
Pneumocystis carinii pneumonia Pneumocystis carinii Lungs (especially prevalent in HIV patients)
Candida albicans GI tract and vagina
infection. Mainly affects CNS.
Fungal cells don’t have cell nucleus and are unlikely the prokaryotic bacteria which can
create potential toxicity problems in the host body. This fungus contains many enzymes
which can be responsible for many miscellaneous transformations in the human cell. These
enzymes are difficult to inhibit by using one potent drug.
4.3.1 Mechanisms of Antifungal Action
Fungal cells are known as complex microorganisms which are able to share many
biochemical targets with other eukaryotic cells as well. The fungal cell wall is unique
organelles which contain the selective toxicity criteria (Fig. 4.4).
Mannoprotein
-Glucan/Chitin
-Glucan
Plasma membrane
Fig. 4.4: Fungal cell wall