Sulphonamides
Dr.Amal Belaid
3
 One of the oldest antibacterial agents used to
combat infection
 Used for coccal infection in 1935
 They are bacteriostatic because it inhibits
bacterial synthesis of folic acid
 Clinical usefulness has decreased because of the effectiveness of
other antibiotics and penicillin
• Building on Ehrlich’s early work, Gerhard Domagk, a medical doctor employed
by a German dye manufacturer made a breakthrough discovery by finding that
a dye known as prontosil, dosed orally, was effective in curing life threatening
streptococci infections in humans. He made the discovery in a desperate, but
successful attempt to save his daughter who was dying of a streptococci
infection.
 First compounds found to be effective antibacterial agents in safe
dose ranges. Chemically, it is a molecule containing the sulfonamido
(sulfanilamide, SO2NH2) functional group attached to an aniline.
 Structurally related to p-amino benzoic acid (PABA). This group is
also present in other non-antibacterial compounds like Sulphonureas -Benzothiazids -Furosemide -Acetazolamide They act
as antimicrobial agents by inhibiting bacterial growth and activity
and commonly called sulfa drugs.
Chemical modification of the sulphonamide structure has
given rise to several important group of drugs.
Gloucoma – Acetazolamide
Diuretic – Thiazides
Anti-mycobacterial – Sulphones
Oral hypoglycemic – Sulphonyl ureas
Mechanism of action
 Competitive inhibitor to dihydropteroate synthase enzyme
due to resemblance with para-amino benzoic acid.
 Sulfonamides therefore are reversible inhibitors of folic
acid synthesis and bacteriostatic not bactericidal.
Inhibit bacterial growth without affecting normal cells
Sulfonamide molecular structure is similar to p-Amino benzoic acid (PABA)
which is needed in bacteria organisms as a substrate of the enzyme dihydro
pteroate synthetase for the synthesis of Tetra Hydro Folic acid (THF). Folic
acid - synthesized from PABA, pteridine and glutamate. All sulfonamides are
analogs of PABA. All sulfa drugs are bacteriostatic
Antibacterial activity
• Gram-positive and gram negative.
• Nocardia, chlamydia trachomatis, some protozoa.
Classification of SA
A. Sulphonamides employed for treatment of systemic
infection. Depending upon duration , they can be further
subdivided into:
a) Short to intermediate acting sulphonamides. Sulfadiazine (Short
acting sulfonamide)• Absorption: Rapid oral absorption. It has good penetrability
inbrain and CSF-was the preferred compound for meningitis.• Metabolism: Liver by
acetylation. It is 50% plasma proteinbound and 20-40% acetylated.• Excretion: Trough
urine.
Sulfamethoxazole (Intermediate acting)• Absorption: Slow oral absorption. It
is the Preferredcompound for combining with trimethoprim because the
t1/2of both is similar.• Metabolism: Liver by acetylation.• Excretion: Trough
urine. Acetylated fraction ofsulfamethoxazole is relatively insolublecrystalluria can occur
Sulfadoxine, Sulfamethopyrazine(Long acting)• These are ultralong acting compounds,
action lasting > 1 weekbecause of high plasma protein binding and slow renalexcretion
(t1/2 5-9 days).• They attain low plasma concentration (of free form) and arenot suitable
for treatment of acute pyogenic infections. Theyare used in combination with
pyrimethamine in the treatmentof malaria
Sulfacetamide sodium(Special purpose sulfonamides)• Highly soluble compound - Mildly
irritating to the eye(concentrations up to 30%).• Used topically for ocular bacterial
infections and chlamydia
Sliver sulfadiazine(Special purpose sulfonamides)• Its act against large number of
bacteria and fungi, even thoseresistance to other sulfonamides (e.g.: Pseudomonas).•
Slow releases silver ions which appear to be largelyresponsible for the antimicrobial
action.
B. Long acting sulphonamides
C. Extra long acting sulphonamides
2. Poorly absorbed sulphonamides
3. Topically used sulphonamides
Structure activity relationship
General
1.Sulphonamide skeleton is the minimum structural
requirement for antibacterial activity.
2.The active form of sulphonamide is the ionized form.
Maximum activity is observed bretween the pka value
6.6-7.4.
3. Sulphonamides competes for binding site on plasma albumin
with causes increased action of drugs like Aspirin,
Phenylbutazone, methotrexate etc.
Therapeutic uses
• Urinary tract infections
• Upper respiratory tract infections
• Nocardiosis
• Sulfasalazine in IBD.
• Sulfacetamide in bacterial conjunctivitis & trachoma
• Silver sulfadiazine for prevention of infection of
burn wounds .
Adverse effects
• Hypersensitivity reactions
• Crystalluria,hematuria,renal obstruction.
• Allergic nephritis
• Haemolytic anaemia, aplastic anaemia, thrombocytopenia.
• Kernicterus in new born
Trimethoprim - Sulfamethoxazole combination
(Co-trimoxazole)
Mechanism of action:
Sequential blocking of purine synthesis
(synergism).
 Trimethoprim inhibits dihydrofolate reductase
enzyme so inhibits tetrahydrofolic acid synthesis
 The combination is bactericidal