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7/19/2012




                                    By- Jitendra Bhangale
                                  Assistant Professor & Head,
                                 Department of Pharmacology,
                              Smt N. M. Padalia Pharmacy College,
                                          Ahmedabad
                                                                                     1
                             © 2010 Delmar, Cengage Learning




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 Bhangale
Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad2
                            © 2010 Smt N. M. Padalia




                                                                                                 1
7/19/2012




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.
                               By Jitendra Bhangale
Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad3
                            © 2010 Smt N. M. Padalia




 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 Bhangale
Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad4
                            © 2010 Smt N. M. Padalia




                                                                                                      2
7/19/2012




                                                           Para-amino-benzoic acid

                                                   Dihydopteroate                 -
Sulfonamides,                   structural          synthetase
                                                                              Sulfonamide
analogs        and              competitive                          Folate

antagonists                of             para-       Dihydofolate                 -
                                                       reductase              Trimethoprim
aminobenzoic           acid         (PABA),
                                                              Tetrahydrofolate
prevent       normal               bacterial
utilization    of     PABA          for    the
synthesis        of         folic          acid              Synthesis of DNA
(pteroylglutamic acid).

                                                             Growth of bacteria

                                By Jitendra Bhangale
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad5
                             © 2010 Smt N. M. Padalia




                                                           Para-amino-benzoic acid

More                           specifically,      Dihydopteroate                 -
                                                     synthetase
sulfonamides are competitive                                                  Sulfonamide
                                                                     Folate
inhibitors     of     dihydropteroate
                                                      Dihydofolate                 -
synthase, the bacterial enzyme                         reductase              Trimethoprim
responsible                for             the                Tetrahydrofolate

incorporation         of    PABA           into
dihydropteroic              acid,          the
                                                             Synthesis of DNA
immediate precursor of folic
acid
                                                             Growth of bacteria

                                By Jitendra Bhangale
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad6
                             © 2010 Smt N. M. Padalia




                                                                                                    3
7/19/2012




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, Delmar, Cengage Learning Pharmacy College, Ahmedabad7
                             © 2010 Smt N. M. Padalia




 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 Bhangale
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad8
                             © 2010 Smt N. M. Padalia




                                                                                                   4
7/19/2012




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 Bhangale
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad9
                             © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                      10
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                  5
7/19/2012




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 Bhangale
                                                                                       11
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                       12
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                   6
7/19/2012




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 Bhangale
                                                                                       13
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                       14
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                   7
7/19/2012




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 Bhangale
                                                                                      15
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                      16
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                  8
7/19/2012




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 Bhangale
                                                                                      17
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                      18
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                  9
7/19/2012




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 Bhangale
                                                                                       19
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                       20
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                  10
7/19/2012




Disturbances of the Urinary Tract
Acute Hemolytic Anemia
Agranulocytosis
Aplastic Anemia
Hypersensitivity Reactions
Miscellaneous Reactions-
        Anorexia, nausea, and vomiting

                                By Jitendra Bhangale
                                                                                      21
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                By Jitendra Bhangale
                                                                                      22
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                 11
7/19/2012




Chlamydia diphtheriae                         Enterobacter spp.,

N. Meningitidis                               Salmonella, Shigella,

S. Pneumoniae,                                Pseudomonas pseudomallei,

Staphylococcus aureus,                         Klebsiella spp.,

Staphylococcus epidermidis,                   Brucella abortus,

S. pyogenes,                                  Pasteurella haemolytica,

E. coli,                                       Yersinia pseudotuberculosis,

Proteus mirabilis,                             Yersinia enterocolitica,

Proteus morganii,                             Nocardia asteroides.

                                 By Jitendra Bhangale
                                                                                       23
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




Sulfonamide    inhibits   the                              Para-amino-benzoic acid
incorporation     of     para-
                                                    Dihydopteroate                 -
aminobenzoic acid (PABA) into                         synthetase
folic acid                                                                     Sulfonamide
                                                                      Folate
Trimethoprim prevents the
                                                       Dihydofolate                 -
reduction of dihydrofolate to                           reductase              Trimethoprim
tetrahydrofolate.
                                                               Tetrahydrofolate

Tetrahydrofolate is essential
for     one-carbon    transfer
reactions
                                                              Synthesis of DNA

Trimethoprim is a                highly
selective      inhibitor              of
dihydrofolate reductase                                       Growth of bacteria

                                 By Jitendra Bhangale
                                                                                       24
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                    12
7/19/2012




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 Bhangale
                                                                                      25
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




      Urinary Tract Infections

      Bacterial Respiratory Tract Infections

      Gastrointestinal Infections

      Infection by Pneumocystis jiroveci

      Miscellaneous Infections



                                By Jitendra Bhangale
                                                                                      26
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                 13
7/19/2012




Megaloblastosis, leukopenia, or thrombocytopenia


Dermatitis, toxic epidermal necrolysis


Stomatitis


Patients with AIDS frequently have hypersensitivity reactions


Rash, neutropenia, pulmonary infiltrates



                                By Jitendra Bhangale
                                                                                      27
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                By Jitendra Bhangale
                                                                                      28
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                 14
7/19/2012




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 Bhangale
                                                                                      29
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                      30
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                 15
7/19/2012




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 Bhangale
                                                                                       31
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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 Bhangale
                                                                                       32
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                  16
7/19/2012




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 Bhangale
                                                                                      33
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                By Jitendra Bhangale
                                                                                      34
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                 17
7/19/2012




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 Bhangale
                                                                                       35
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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 FQs
Resistance         has       been         reported           among          Salmonella,
        Pseudomonas, staphylococci and pneumococci.
                                By Jitendra Bhangale
                                                                                      36
 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                             © 2010 Smt N. M. Padalia




                                                                                                  18
7/19/2012




              CLASSIFICATION OF FLUOROQUINOLONES



1st generation fluoroquinolone                 2nd generation fluoroquinolones

                                               Lomefloxacin
Norfloxacin
                                               Sparfloxacin
Ofloxacin
                                               Levofloxacin
Ciprofloxacin                                 Gatifloxacin

Pefloxacin                                    Moxifloxacin

                                 By Jitendra Bhangale
                                                                                       37
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




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.


Highly susceptible
                                               Neisseria gonorrhoeae
E. Coli
                                               N. meningitdis
S. pneumoniae
                                               H. Influenzae
Enterobacter
                                               Campylobacter jejuni
Salmonella typhi
                                               Yersinia enterocolitica
Shigella
                                               Vibrio cholerae
Proteus
                                 By Jitendra Bhangale
                                                                                       38
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                  19
7/19/2012




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 Bhangale
                                                                                       39
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                Therapeutic Uses


                                               Bone, soft tissue and wound
Urinary tract infection
                                                         infections
Gonorrhoe
                                               Respiratory infections
Chancroid
                                               Tuberurlosis
Bacterial gastroenteritis
                                               Meningitis
Typhoid
                                                Conjunctivitis
                                 By Jitendra Bhangale
                                                                                       40
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                  20
7/19/2012




Examples: -                  Lomefloxacin,                 Sparfloxacin,
           Levofloxacin ,              Gatifloxacin,                 Moxifloxacin

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 Bhangale
                                                                                       41
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                 By Jitendra Bhangale
                                                                                       42
  Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
                              © 2010 Smt N. M. Padalia




                                                                                                  21

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Sulfonamides, quinolones and fluoroquinolones BY JITENDRA BHANGALE

  • 1. 7/19/2012 By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage Learning 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 Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad2 © 2010 Smt N. M. Padalia 1
  • 2. 7/19/2012 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. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad3 © 2010 Smt N. M. Padalia 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 Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad4 © 2010 Smt N. M. Padalia 2
  • 3. 7/19/2012 Para-amino-benzoic acid Dihydopteroate - Sulfonamides, structural synthetase Sulfonamide analogs and competitive Folate antagonists of para- Dihydofolate - reductase Trimethoprim aminobenzoic acid (PABA), Tetrahydrofolate prevent normal bacterial utilization of PABA for the synthesis of folic acid Synthesis of DNA (pteroylglutamic acid). Growth of bacteria By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad5 © 2010 Smt N. M. Padalia Para-amino-benzoic acid More specifically, Dihydopteroate - synthetase sulfonamides are competitive Sulfonamide Folate inhibitors of dihydropteroate Dihydofolate - synthase, the bacterial enzyme reductase Trimethoprim responsible for the Tetrahydrofolate incorporation of PABA into dihydropteroic acid, the Synthesis of DNA immediate precursor of folic acid Growth of bacteria By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad6 © 2010 Smt N. M. Padalia 3
  • 4. 7/19/2012 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, Delmar, Cengage Learning Pharmacy College, Ahmedabad7 © 2010 Smt N. M. Padalia 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 Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad8 © 2010 Smt N. M. Padalia 4
  • 5. 7/19/2012 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 Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad9 © 2010 Smt N. M. Padalia 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 Bhangale 10 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 5
  • 6. 7/19/2012 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 Bhangale 11 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 12 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 6
  • 7. 7/19/2012 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 Bhangale 13 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 14 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 7
  • 8. 7/19/2012 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 Bhangale 15 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 16 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 8
  • 9. 7/19/2012 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 Bhangale 17 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 18 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 9
  • 10. 7/19/2012 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 Bhangale 19 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 20 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 10
  • 11. 7/19/2012 Disturbances of the Urinary Tract Acute Hemolytic Anemia Agranulocytosis Aplastic Anemia Hypersensitivity Reactions Miscellaneous Reactions- Anorexia, nausea, and vomiting By Jitendra Bhangale 21 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 22 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 11
  • 12. 7/19/2012 Chlamydia diphtheriae Enterobacter spp., N. Meningitidis Salmonella, Shigella, S. Pneumoniae, Pseudomonas pseudomallei, Staphylococcus aureus,  Klebsiella spp., Staphylococcus epidermidis, Brucella abortus, S. pyogenes, Pasteurella haemolytica, E. coli,  Yersinia pseudotuberculosis, Proteus mirabilis,  Yersinia enterocolitica, Proteus morganii, Nocardia asteroides. By Jitendra Bhangale 23 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Sulfonamide inhibits the Para-amino-benzoic acid incorporation of para- Dihydopteroate - aminobenzoic acid (PABA) into synthetase folic acid Sulfonamide Folate Trimethoprim prevents the Dihydofolate - reduction of dihydrofolate to reductase Trimethoprim tetrahydrofolate. Tetrahydrofolate Tetrahydrofolate is essential for one-carbon transfer reactions Synthesis of DNA Trimethoprim is a highly selective inhibitor of dihydrofolate reductase Growth of bacteria By Jitendra Bhangale 24 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 12
  • 13. 7/19/2012 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 Bhangale 25 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Urinary Tract Infections Bacterial Respiratory Tract Infections Gastrointestinal Infections Infection by Pneumocystis jiroveci Miscellaneous Infections By Jitendra Bhangale 26 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 13
  • 14. 7/19/2012 Megaloblastosis, leukopenia, or thrombocytopenia Dermatitis, toxic epidermal necrolysis Stomatitis Patients with AIDS frequently have hypersensitivity reactions Rash, neutropenia, pulmonary infiltrates By Jitendra Bhangale 27 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 28 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 14
  • 15. 7/19/2012 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 Bhangale 29 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 30 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 15
  • 16. 7/19/2012 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 Bhangale 31 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 Bhangale 32 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 16
  • 17. 7/19/2012 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 Bhangale 33 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 34 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 17
  • 18. 7/19/2012 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 Bhangale 35 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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 FQs Resistance has been reported among Salmonella, Pseudomonas, staphylococci and pneumococci. By Jitendra Bhangale 36 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 18
  • 19. 7/19/2012 CLASSIFICATION OF FLUOROQUINOLONES 1st generation fluoroquinolone 2nd generation fluoroquinolones Lomefloxacin Norfloxacin Sparfloxacin Ofloxacin Levofloxacin Ciprofloxacin Gatifloxacin Pefloxacin Moxifloxacin By Jitendra Bhangale 37 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 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. Highly susceptible Neisseria gonorrhoeae E. Coli N. meningitdis S. pneumoniae H. Influenzae Enterobacter Campylobacter jejuni Salmonella typhi Yersinia enterocolitica Shigella Vibrio cholerae Proteus By Jitendra Bhangale 38 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 19
  • 20. 7/19/2012 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 Bhangale 39 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Therapeutic Uses Bone, soft tissue and wound Urinary tract infection infections Gonorrhoe Respiratory infections Chancroid Tuberurlosis Bacterial gastroenteritis Meningitis Typhoid Conjunctivitis By Jitendra Bhangale 40 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 20
  • 21. 7/19/2012 Examples: - Lomefloxacin, Sparfloxacin, Levofloxacin , Gatifloxacin, Moxifloxacin 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 Bhangale 41 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 42 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 21