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7/19/2012
1
© 2010 Delmar, Cengage Learning1
By- Jitendra Bhangale
Assistant Professor & Head,
Department of Pharmacology,
Smt N. M. Padalia Pharmacy College,
Ahmedabad
© 2010 Delmar, Cengage Learning2
Sulphonamide derived from prontosil (prodrug)
1932 Gerhard Domagk
Discovered protective aspects of Prontosil (azo dye).
1933 Prontosil given to 10 month old girl who survived
1935 Sulfa first used in US unsuccessfully
Late 1930’s sulfanilamide derivatives synthesized
Increase efficacy and decrease side effects
1968 Sulfa combined with Trimethoprim
Sulfonamides also called sulfanilamides or sulfa drugs.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning3
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
All sulfonamides may be considered to be derivatives of
sulfanilamide (p-aminobenzene sulfonamides).
All the drugs individually differ in their nature of N1 substitution,
which governs pharmacokinetic property.
A free amino group in the para position N4 is required for
antibacterial activity.
© 2010 Delmar, Cengage Learning4
Sulfonamides are primarily bacteriostatic against many gram
+ve and –ve bacteria.
Microorganisms that may be susceptible in vitro to
sulfonamides include Streptococcus pyogenes, Streptococcus
pneumoniae, Haemophilus influenzae, Haemophilus ducreyi,
Nocardia, Actinomyces, Calymmatobacterium granulomatis,
Vibrio cholerae , Staphylococcus aureus, and Chlamydia
trachomatis.
Sulfonamides were used successfully for the management of
meningococcal infections for many years, the majority of
isolates of Neisseria meningitidis
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
3
© 2010 Delmar, Cengage Learning5
Sulfonamides, structural
analogs and competitive
antagonists of para-
aminobenzoic acid (PABA),
prevent normal bacterial
utilization of PABA for the
synthesis of folic acid
(pteroylglutamic acid).
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Para-amino-benzoic acid
Folate
Tetrahydrofolate
Synthesis of DNA
Growth of bacteria
Dihydopteroatesynthetase
Dihydofolatereductase
Sulfonamide
Trimethoprim
-
-
© 2010 Delmar, Cengage Learning6
More specifically,
sulfonamides are competitive
inhibitors of dihydropteroate
synthase, the bacterial enzyme
responsible for the
incorporation of PABA into
dihydropteroic acid, the
immediate precursor of folic
acid
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Para-amino-benzoic acid
Folate
Tetrahydrofolate
Synthesis of DNA
Growth of bacteria
Dihydopteroatesynthetase
Dihydofolatereductase
Sulfonamide
Trimethoprim
-
-
7/19/2012
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© 2010 Delmar, Cengage Learning7
Bacteria resistant to sulfonamides is presumed to originate by
random mutation and selection or by transfer of resistance
by plasmids.
Resistance to sulfonamide probably is the consequence of an
altered enzymatic constitution of the bacterial cell; and may
be characterized by
lower affinity for sulfonamides by dihydropteroate synthase,
decreased bacterial permeability or active efflux of the drug,
an alternative metabolic pathway for synthesis of an essential
metabolite,
increased production of an essential metabolite or drug
antagonist.By Jitendra Bhangale
Asst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning8
Absorption
This class of drugs is absorbed rapidly from the gastrointestinal
tract.
The small intestine is the major site of absorption, but some of
the drug is absorbed from the stomach.
Absorption from other sites, such as the vagina,
respiratory tract, or abraded skin, is variable and
unreliable.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning9
Distribution
Sulfonamides are distributed throughout all tissues of the body.
Sulfonamides pass readily through the placenta and reach the
fetal circulation.
Elimination
Sulfonamides are eliminated from the body partly as the
unchanged drug and partly as metabolic products. The
largest fraction is excreted in the urine.
Small amounts are eliminated in the feces, bile, milk, and other
secretions.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning10
The sulfonamides may be classified on the basis of the rapidity
with which they are absorbed and excreted:
1. Agents that are absorbed and excreted rapidly,
such as sulfisoxazole and sulfadiazine;
2. Agents that are absorbed very poorly when administered orally
and hence are active in the bowel lumen,
such as sulfasalazine;
3. Agents that are used mainly topically,
such as sulfacetamide, mafenide, & silver sulfadiazine;
4. Long-acting sulfonamides, that are absorbed rapidly but
excreted slowly such as sulfadoxine & sulfamethopyrazine
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning11
Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with
excellent antibacterial activity.
Sulfisoxazole is bound extensively to plasma proteins.
Sulfisoxazole acetyl is tasteless and hence preferred for oral use in
children. Sulfisoxazole acetyl is marketed in combination with
erythromycin ethylsuccinate for use in children with otitis
media.
The urine becomes orange-red soon after ingestion of this mixture
because of the presence of phenazopyridine, an orange-red dye.
Unwanted effetct:
Hematuria or crystalluria (0.2% to 0.3%), hypersensitivity reactions
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning12
Sulfamethoxazole is a close congener of sulfisoxazole, but its
rates of enteric absorption and urinary excretion are slower.
It is administered orally and employed for both systemic and
urinary tract infections.
Precautions must be observed to avoid sulfamethoxazole
crystalluria
The clinical uses of sulfamethoxazole are the same as those for
sulfisoxazole.
It also is marketed in fixed-dose combinations with trimethoprim.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning13
Sulfadiazine given orally is absorbed rapidly from the GI tract.
Sulfadiazine is excreted quite readily by the kidney in both the
free and acetylated forms, rapidly at first and then more slowly over
a period of 2 to 3 days.
In adults and children who are being treated with sulfadiazine,
every precaution must be taken to ensure fluid intake adequate to
produce a urine output of at least 1200 ml in adults.
If this cannot be accomplished, sodium bicarbonate may be given
to reduce the risk of crystalluria.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning14
Sulfasalazine is very poorly absorbed from the GI tract.
It is used in the therapy of ulcerative colitis and regional enteritis.
Corticosteroids are more effective in treating acute attacks, but
sulfasalazine is preferred to corticosteroids for the treatment
of patients who are mildly or moderately ill with ulcerative
colitis.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning15
Sulfasalazine is broken down by intestinal bacteria to
sulfapyridine, an active sulfonamide that is absorbed and
eventually excreted in the urine, and 5-aminosalicylate,
which reaches high levels in the feces. 5-Aminosalicylate is
the effective agent in inflammatory bowel disease, whereas
sulfapyridine is responsible for most of the toxicity.
Toxic reactions include Heinz-body anemia, acute hemolysis in
patients with glucose-6-phosphate dehydrogenase
deficiency, and agranulocytosis. Nausea, fever, arthralgias
Sulfasalazine can cause a reversible infertility in males.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning16
Its aqueous solubility (1:140) is approximately 90 times that of
sulfadiazine.
Solutions of the sodium salt are employed extensively in the
management of ophthalmic infections.
Although topical sulfonamide for most purposes is discouraged
because of lack of efficacy and a high risk of sensitization,
sulfacetamide has certain advantages.
Very high aqueous concentrations are not irritating to the eye
and are effective against susceptible microorganisms.
The drug should not be used in patients with known
hypersensitivity to sulfonamides.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
9
© 2010 Delmar, Cengage Learning17
Silver sulfadiazine inhibits the growth in vitro of nearly all
pathogenic bacteria and fungi, including some species
resistant to sulfonamides.
The compound is used topically to reduce microbial colonization
and the incidence of infections of wounds from burns.
Silver is released slowly from the preparation in concentrations
that are selectively toxic to the microorganisms.
Adverse reactions burning, rash, and itching are infrequent.
Silver sulfadiazine is considered by most authorities to be one of
the agents of choice for the prevention of burn infection.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning18
When applied topically, it is effective for the prevention of
colonization of burns by a large variety of gram-negative and
gram-positive bacteria.
It should not be used in treatment of an established deep
infection.
The cream is applied once or twice daily to a thickness of 1 to 2
mm over the burned skin.
Cleansing of the wound and removal of debris should be carried
out before each application of the drug.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning19
Therapy is continued until skin grafting is possible.
Mafenide is rapidly absorbed systemically and converted to para-
carboxybenzenesulfonamide.
Adverse effects include intense pain at sites of application, allergic
reactions.
The drug and its primary metabolite inhibit carbonic anhydrase,
and the urine becomes alkaline.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning20
Sulfadoxine has a particularly long half-life (7 to 9 days).
It is used in combination with pyrimethamine for the
prophylaxis and treatment of malaria caused by mefloquine -
resistant strains of Plasmodium falciparum
Because of severe and sometimes fatal reactions, including the
Stevens-Johnson syndrome, the drug should be used for
prophylaxis only where the risk of resistant malaria is high.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
11
© 2010 Delmar, Cengage Learning21
Disturbances of the Urinary Tract
Acute Hemolytic Anemia
Agranulocytosis
Aplastic Anemia
Hypersensitivity Reactions
Miscellaneous Reactions-
Anorexia, nausea, and vomiting
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning22
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning23
Chlamydia diphtheriae
N. Meningitidis
S. Pneumoniae,
Staphylococcus aureus,
Staphylococcus epidermidis,
S. pyogenes,
E. coli,
Proteus mirabilis,
Proteus morganii,
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Enterobacter spp.,
Salmonella, Shigella,
Pseudomonas pseudomallei,
Klebsiella spp.,
Brucella abortus,
Pasteurella haemolytica,
Yersinia pseudotuberculosis,
Yersinia enterocolitica,
Nocardia asteroides.
© 2010 Delmar, Cengage Learning24
Sulfonamide inhibits theincorporation of para-aminobenzoic acid (PABA) intofolic acid
Trimethoprim prevents thereduction of dihydrofolate totetrahydrofolate.
Tetrahydrofolate is essentialfor one-carbon transferreactions
Trimethoprim is a highlyselective inhibitor ofdihydrofolate reductase
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Para-amino-benzoic acid
Folate
Tetrahydrofolate
Synthesis of DNA
Growth of bacteria
Dihydopteroatesynthetase
Dihydofolatereductase
Sulfonamide
Trimethoprim
-
-
7/19/2012
13
© 2010 Delmar, Cengage Learning25
After a single oral dose of the combined preparation,
trimethoprim is absorbed more rapidly than
sulfamethoxazole.
When 800 mg sulfamethoxazole is given with 160 mg
trimethoprim (the conventional 5:1 ratio) twice daily.
Trimethoprim is distributed and concentrated rapidly in
tissues, and about 40% is bound to plasma protein in
the presence of sulfamethoxazole. The volume of
distribution of trimethoprim is almost nine times that
of sulfamethoxazole.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning26
Urinary Tract Infections
Bacterial Respiratory Tract Infections
Gastrointestinal Infections
Infection by Pneumocystis jiroveci
Miscellaneous Infections
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning27
Megaloblastosis, leukopenia, or thrombocytopenia
Dermatitis, toxic epidermal necrolysis
Stomatitis
Patients with AIDS frequently have hypersensitivity reactions
Rash, neutropenia, pulmonary infiltrates
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning28
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning29
These are synthetic antimicrobials having a quinolone structure
that are active primarily against gram-negative bacteria,
though newer fluorinated compounds also inhibit gram-
positive ones.
The first member Nalidixic acld introduced in mid-1960s
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning30
Nalidixic acid
Antibacterial spectrum
It is active against gram-negative bacteria, especially coliforms: E.
coli, Proteus, Klebsiella, Enterobacter, Shigella but not
Pseudomonas.
Pharmacokinetics
Nalidixic acid is absorbed orally, highly plasma protein bound
and partly metabolized in liver.
It is excreted in urine.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning31
Mechanism of action
The quinolone antibiotics target bacterial DNA gyrase and
topoisomerase IV.
For many gram-positive bacteria (such as S. aureus),
topoisomerase IV is the primary activity inhibited by the
quinolones.
In contrast, for many gram-negative bacteria (such as E. coli),
DNA gyrase is the primary quinolone target.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning32
The enzyme binds to two segments of DNA (1), creating a node of positive
(+) superhelix. The enzyme then introduces a double-strand break
in the DNA and passes the front segment through the break (2). The
break is then resealed (3), creating a negative (-) supercoil.
Quinolones inhibit the nicking and closing activity of the gyrase and also
block the decatenating activity of topoisomerase IV.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning33
Adverse effects
G.I. upset and rashes, neurological-headache, drowsiness, vertigo,
visual disturbances, occasionally seizures (especially in
children).
Individuals with G-6-PD deficiency may develop haemolysis.
Nalidixic acid is contraindicated in infants.
Therapeutic uses
Nalidixic acid is primarily used as a urinary antiseptic
It has also been employed in diarrhoea caused by Proteus, E . coli,
Shigella or Salmonella, and has a special place in ampicillin
resistant Shigella enteritis.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning34
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning35
Mechanism of action
The FQs inhibit the enzyme bacterial DNA topoisomerase IV,
which nicks double-stranded DNA, introduces negative supercoils
and then reseals the nicked ends.
This is necessary to prevent excessive positive supercoiling of the
strands when they separate to permit replication or
transcription.
The DNA gyrase consists of two A and two B subunits: The A
subunit carries out nicking of DNA, B subunit introduces
negative supercoils and then A subunit reseals the strands.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning36
FQs bind to A subunit with high affinity and interfere with its
strand cutting and resealing function.
Recent evidence indicates that in gram-positive bacteria the major
target of FQ action is a similar enzyme topoisomerase IV
which nicks and separates daughter DNA strands after DNA
replication.
Mechanism of resistance
Resistance noted so far is due to chromosomal mutation
producing a DNA gyrase or topoisomerase IV with reduced
affinity for FQsResistance has been reported among Salmonella,
Pseudomonas, staphylococci and pneumococci.By Jitendra Bhangale
Asst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
7/19/2012
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© 2010 Delmar, Cengage Learning37
1st generation fluoroquinolone
Norfloxacin
Ofloxacin
Ciprofloxacin
Pefloxacin
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
2nd generation fluoroquinolones
Lomefloxacin
Sparfloxacin
Levofloxacin
Gatifloxacin
Moxifloxacin
CLASSIFICATION OF FLUOROQUINOLONES
© 2010 Delmar, Cengage Learning38
Highly susceptible
E. Coli
S. pneumoniae
Enterobacter
Salmonella typhi
Shigella
Proteus
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Neisseria gonorrhoeae
N. meningitdis
H. Influenzae
Campylobacter jejuni
Yersinia enterocolitica
Vibrio cholerae
It is the most potent first generation FQ active against a broad range
of bacteria, the most susceptible ones are the aerobic gram negative
bacilli, especially the Enterobacteriaceae and Neisseria.
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© 2010 Delmar, Cengage Learning39
Notable resistant bacteria are: Bacteroides fragilis, Clostridia,
anaerobic cocci.
Adverse effects
Gastrointestinal: nausea, vomiting, bad taste, anorexia.
CNS: dizziness, headache, restlessness, anxiety, insomnia.
Skin/hypersensitivity: rash, pruritus, photosensitivity, urticaria,
swelling of lips, etc.
Ciprofloxacin and other FQs are contraindicated during
pregnancy.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
© 2010 Delmar, Cengage Learning40
Urinary tract infection
Gonorrhoe
Chancroid
Bacterial gastroenteritis
Typhoid
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Bone, soft tissue and wound
infections
Respiratory infections
Tuberurlosis
Meningitis
Conjunctivitis
Therapeutic Uses
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© 2010 Delmar, Cengage Learning41
This second generation difluorinated quinolone has enhanced
activity against gram-positive bacteria (especially Strep.
Pneumoniae, Staphylococcus Enterococcus), Bacteroides fragilis,
other anaerobes and mycobacteria.
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad
Examples: - Lomefloxacin, Sparfloxacin,
Levofloxacin , Gatifloxacin, Moxifloxacin
© 2010 Delmar, Cengage Learning42
By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad