Sulfonamides, quinolones and fluoroquinolones BY JITENDRA BHANGALE

7/19/2012

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© 2010 Delmar, Cengage Learning1

By- Jitendra Bhangale

Assistant Professor & Head,

Department of Pharmacology,

Smt N. M. Padalia Pharmacy College,

Ahmedabad


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

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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.


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


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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).


Para-amino-benzoic acid

Folate

Tetrahydrofolate

Synthesis of DNA

Growth of bacteria

Dihydopteroatesynthetase

Dihydofolatereductase

Sulfonamide

Trimethoprim

-

-


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



Folate

Tetrahydrofolate

Synthesis of DNA

Growth of bacteria



Sulfonamide

Trimethoprim

-

-

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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


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.


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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.



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


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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



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.


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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.



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.


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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.



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.


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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.



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.


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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.



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.


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Disturbances of the Urinary Tract

Acute Hemolytic Anemia

Agranulocytosis

Aplastic Anemia

Hypersensitivity Reactions

Miscellaneous Reactions-

Anorexia, nausea, and vomiting




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Chlamydia diphtheriae

N. Meningitidis

S. Pneumoniae,

Staphylococcus aureus,

Staphylococcus epidermidis,

S. pyogenes,

E. coli,

Proteus mirabilis,

Proteus morganii,


Enterobacter spp.,

Salmonella, Shigella,

Pseudomonas pseudomallei,

Klebsiella spp.,

Brucella abortus,

Pasteurella haemolytica,

Yersinia pseudotuberculosis,

Yersinia enterocolitica,

Nocardia asteroides.


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



Folate

Tetrahydrofolate

Synthesis of DNA

Growth of bacteria



Sulfonamide

Trimethoprim

-

-

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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.



Urinary Tract Infections

Bacterial Respiratory Tract Infections

Gastrointestinal Infections

Infection by Pneumocystis jiroveci

Miscellaneous Infections


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Megaloblastosis, leukopenia, or thrombocytopenia

Dermatitis, toxic epidermal necrolysis

Stomatitis

Patients with AIDS frequently have hypersensitivity reactions

Rash, neutropenia, pulmonary infiltrates




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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



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.


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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.



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.


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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.




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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.



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

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1st generation fluoroquinolone

Norfloxacin

Ofloxacin

Ciprofloxacin

Pefloxacin


2nd generation fluoroquinolones

Lomefloxacin

Sparfloxacin

Levofloxacin

Gatifloxacin

Moxifloxacin

CLASSIFICATION OF FLUOROQUINOLONES


Highly susceptible

E. Coli

S. pneumoniae

Enterobacter

Salmonella typhi

Shigella

Proteus


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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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.



Urinary tract infection

Gonorrhoe

Chancroid

Bacterial gastroenteritis

Typhoid


Bone, soft tissue and wound

infections

Respiratory infections

Tuberurlosis

Meningitis

Conjunctivitis

Therapeutic Uses

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This second generation difluorinated quinolone has enhanced

activity against gram-positive bacteria (especially Strep.

Pneumoniae, Staphylococcus Enterococcus), Bacteroides fragilis,

other anaerobes and mycobacteria.


Examples: - Lomefloxacin, Sparfloxacin,

Levofloxacin , Gatifloxacin, Moxifloxacin



Education

Sulfonamides, quinolones and fluoroquinolones BY JITENDRA BHANGALE