1. SULPHONAMIDES
GUIDE:
Mrs. T. PRABHA
ASISSITANT PROFESSOR
DEPARTMENT OF PHARMACEUTICAL ANALYSIS
NANDHA COLLEGE OF PHARMACY
ERODE-52
AMEERA.N
III PHARM D
NANDHA COLLEGE OF PHARMACY
ERODE-52
2. Sulfonamides derived from p-amino benzene sulfonamide.
It is the first chemotherapeutic agents implied systematically for prevention of bacterial
infections.
HISTORY:
Screening of ‘dyes’ for their actibacterial properties in 1920s.
Sulfonamido-chrysidine-commonly known as “prontosil red” was the first one effective in
streptococcal infection in mice by Domagk.
cured his daughter.
1937-prontosil was broken down to release “sulfanilamide”-many sulfonamides were produced.
3. CHEMISTRY OF SULPHONAMIDES:
■ Recognised since 1932.
■ In clinical usage since 1935.
■ First compound found to be effective antibacterial agents in safe dose ranges.
■ Chemically,it is a molecule containing sulfonamide(sulfanilamide , SO2NH2) functional
group attached to an analine.
■ Structurally related to p-amino benzoic acid (PABA).
■ This group is also present in other non-antibacterial compound like sulphonureas ,
benzothiazids , furosemide , acetazolamide.
4. NOMENCLACTURE OF THE SULFONAMIDES:
■ Sulfonamides is a generic term that denotes 3 different cases:
1. Antibacterials that are analine-substituted sulfonamides (sulfanilamides)
2. Prodrug that react to generate active sulfanilamides(sulfasalazine)
3. Nonanaline sulfonamides (mefenide acetate)
5. SYNERGISM OF SULFONAMIDE AND FOLATE
REDUCTASE INHIBITORS:
■ If biosynthesis of bacterial folate coenzymes is blocked at more than one point in the
pathway , the result will be a synergistic antimicrobial effect.
■ This is beneficial because the microbe will not develop resistance as readily as it would
with a singly blocked pathway.
■ The synergistic approach is used widely in antibacterial therapy with the combination of
sulfamethoxazole and trimethoprim
■ In antimalarial therapy with pyrimethamine plus a sulfonamide or quinine
.
6. THE PROBLEM OF CRYSTALLURIA
■ Sulfonamides are mostly excreted in urine as acetylated metabolite.
■ They are relatively water insoluble mainly due to the formation of acetylated
metabolites.
■ The acetylated metabolite is non-ionizable under the PH conditions of the urine(~7) that
increase the possibility of precipitation and the formation of crystals in the urine.
How to minimize the possibility of crystalluria formation with
sulfonamides:
Increase the urine flow.
Increase the PH of the urine to increase the ionization of sulfonamides and the formation
of water soluble salts.
7. ■ Lowering the Pka of the sulfonamide group which will help to increase the ionization under the
acidic conditions . This can be done by adding electron withdrawing group on the sulfonamide
side chain.
8. CLASSIFICATION
c)Agents which are employed topically
■ Mefenide
■ Sodium sulfacetamide
■ Silver sulfadiazole
ON THE BASIS OF:
PHARMACOKINETIC
PROPERTIES:
a)Agents which are rapidly absorbed and
excreted:
■ Sulfamethaxazole
■ Sulfisoxazole
■ Sulfapyridine
■ sulfadiazine
b)Agents which are poorly absorbed in
GIT (local):
■ Sulfasalazine
■ Phthalyl sulfathiazole
9.
10.
11. STRUCTURALACTIVITY RELATIONSHIP:
■ The amino and sulfonyl radicle on benzene ring are essential for the activity and should be in 1 ,4 position.
■ The 4 amino group should be modified to produce prodrug which are converted into 3-amino functional group
invivo.
eg: phthalyl sulfathiazole
succinyl sulfathiazole
■ Replacement of benzene ring by another ring system or the introduction of additional subsituent on benzene
ring will decrease the activity.
■ Exchange of sulfonyl group (-SO2NH2) by other group like SO2C6H4(-P-NH2) ,CONH2,
CONHR, COC6H4R, to retain the activity.
12. ■ Subsitution of hectrocyclic aromatic nuclei at 1st position yield highly potent compound.
■ 1st position disubsitution in general leads to inactive compound because one hydrogen is
needed for ionization.
■ The pi charge of first position activity greater the charge greater the activity.
■ The protein binding like arginine, histidine, lysine, on basic center of sulfonamide will
affect the activity,because protein binding appear to modulate the bioavailability of drug
and its t1/2.
14. ■ Sulfonamides and sulfones in antibacterial agents act as a
competitive inhibitor for incoperation of PABA to form
dihydropteroic acid.
■ The 1st position substitution in sulphonamide compete for site on
enzyme surface reserved for glutamate residue.
■ It compete for linking of PABA glutamate with pteridine
derivative.
■ Trimethoprim is a structural analogue of dihydrofolic acid.It is a
selective competitive inhibitor of microbial folate reductase,the
enzyme that reduces dihydrofolate to tetrahydrofolate.
■ Simultaneous administration of sulphonamides and trimethoprim
block the pathway of synthesis of tetrahydrofolate and producing
synthetic antimicrobial effect.
20. ADVERSE EFFECTS:
mental/mood changes
extreme drowsiness
sweating
fast heartbeat
USES:
• Used in the treatment of bacterial infection.
• Used in lower urinary tract and systemic infections caused by E.coli and p.Mirabilis.
• Used in combination with trimethoprim is used in treatment of several infections
including AIDS.
• It is also used to prevent and treat a certain type of pneumonia.
27. ADVERSE EFFECT:
unusually fast heartbeat, bluish lips/skin, chest pain, mental/mood changes,
muscle weakness, difficulty urinating.
USES:
used to treat a certain type of skin disorder (dermatitis herpetiformis).
It is also used with other drugs to treat Hansen's disease.
.
SULFASOXAZOLE
STRUCTURE
28. DOSE:
4-6g daily 2-3 divided doses
DOSAGE:
500mg tablet
ADVERSE EFFECT:
Stomach pain , dizziness , rashes , headache , diarrhea
USES:
Used to treat a certain type of bowel diseases called ulcerative colitis.
SULPHAMETHAZINE
STRUCTURE
29. DOSE:
3-4 g daily in divided dose
DOSAGE:
500mg tablet
ADVERSE EFFECT:
Gastric distress , headache , nausea , oligospermia , vomiting , anorexia.
USES:
Used for treatment of bacterial infections causing bronchitis , prostatitis and urinary
tract infection.
Used for pneumococcal ,staphylococcal and streptococcal infections.
Used in sepsis , gonorrhea and other infectious disease.
30. DOSE:
250mg-1g 4 times aday for dermatitis herpetiform.
DOSAGE:
250mg capsule
ADVERSE EFFECT:
Fever , crystalluria ,blood dyscariasis , thyroid function disturbances , hypersensitivity.
USES:
Used for the treatment of dermatitis herpetiformis,pemphigoid,bullous and pyoderma
gangrenosum.
SULFAPYRIDINE
STRUCTURE
31. DOSE:
5% solution of mefenide chloride or mefenide propionate for topical use.
DOSAGE:
Mefenide actetate cream
ADVERSE EFFECT:
Allergic reactions , bleeding or oozing of skin , metabolic acidosis.
USES:
Used alone or with combination with other medication to prevent or treat wound
infections.
Used in the treatment and cure of gas gangrene . Also effective against clostridium
welchii on topical application .
MEFENIDE ACETATE
STRUCTURE
32. DOSE:
2g per day in equally divide dose
DOSAGE:
500 mg tablet
ADVERSE EFFECT:
Decreased appetite , stomach upset or stomach pain , aching of joints , headache , photosensitivity,
rashes.
USES:
Used to treat certain type of bowel disease called ulcerative colitis.
Delayed –release tablets of sulfasalazine used to treat rheumatoid arthritis
SULFASALAZINE
STRUCTURE
33. ADVERSE EFFECT:
Headache , loss of appetite , stomach upset , nausea and vomiting .
USES:
Used as antileprotic drug .It is less potent than dapsone and is used when there is a
gastric intolerance of dapsone.
SOLAPSONE
STRUCTURE
34. MIXED SULFONAMIDES
TRISULFAPYRIMIDINES,ORAL SUSPENSION:
The oral suspension of trisulfapyrimidne contains equal weight of sulfadiazine ,
sulfamerazine and sulfamethazine either with or without an agent to raise the PH of
urine.
TRISULFAPYRIMIDINES,TABLET:
Trisulfapyrimidine tablet contain essentially equal quantities of sulfadiazine ,
sulfamerazine and sulfamethizine .
SULFADOXINE AND PYRIMETHAMINE:
The mixture of sulfadoxine and pyrimethamine is used to treat of P.falciparum
malaria in patients in whom chloroquine resistance is suspected .
It is also used for malaria prophylaxis for travelers to areas where chloroquine-
resistant malaria is endemic.
