Sulfonamides are synthetic antimicrobial agents that act as structural analogues of para-amino benzoic acid (PABA), an important component in bacterial folic acid synthesis. Sulfonamides compete with PABA for the bacterial enzyme dihydropteroic acid synthetase, forming nonfunctional folic acid analogues that inhibit bacterial growth. Common sulfonamide drugs include sulfadiazine, sulfamethoxazole, and sulfadoxine. Cotrimoxazole is a synergistic combination of sulfamethoxazole and trimethoprim that inhibits two sequential steps in bacterial folic acid synthesis. Sulfonamides are selectively toxic to bacteria due to differences in human and bacterial

1. Sulfonamides
Dr. M N Nadeem,
Associate Professor, DCMS,
Pharmacology,
MBBS, MD

2. Introduction to sulfonamides
• Synthetic antimicrobials
• Sulfonamides are Structural analogues of
p-amino benzoic acid (PABA)
• Unlike Humans, bacteria has to synthesize its own
folic acid (from PABA) for its growth and
multiplication.
• Active form of folic acid is:-
– Tetrahydro folic acid (THFA)
• This THFA is an important coenzyme responsible
for the synthesis of bacterial proteins (from
amino acids) and of bacterial RNA and DNA (from
nucleic acids)

3. Bacterial folic acid synthesis

4. Sulfonamides – Mechanism of Action
• Structural analogues of PABA
• Therefore, they enter synthetic sequence in
place of PABA by competing for the enzyme
Dihydropteroic acid synthetase (also called
folic acid synthetase)
• Thus they from a non-functional analogue of
folic acid which is of no use to bacteria.
• Hence, its growth ceases (bacteriostatic
action)

5. Why human cells are not effected by
sulfonamides ?
• Human cells can directly absorb folic acid and
therefore bypass the sulfonamide-induced
block of PABA inclusion.
• Hence sulfonamides are selectively toxic to
the bacteria and not to the host cells.

6. Sulfonamides - Classification
Orally absorbable agents
• Sulfadiazine (Short acting - t1/2 6-9 hrs)
• Sulfamethoxazole (Intermediate acting -t1/2 10-12 hrs)
• Sulfadoxine (Long acting - t1/2 7-8 days)
Orally non-absorbable Agents
• Sulfasalazine
Topical agents
• Silver Sulfadiazine, Sodium Sulfacetamide, Mefanide

7. Synergistic combinations with
Sulfonamides
• Cotrimoxazole (Sulfamethaxazole + Trimethoprim)
• Sulfadoxime + Pyrimethamine
• Sulfadiazine + Pyrimethamine

8. Trimethoprim
• One of the two drugs which make up Cotrimoxazole
• Structural analogue of the pteridine portion of DHFA
• Unlike Sulfonamides, it blocks the conversion of
DHFA to THFA(active form) by competitively
inhibiting the enzyme Dihydrofolate reductase
(DHFR).
• Trimethoprim doesn’t effect human cells, as It has
much higher affinity for bacterial DHFR compared to
protozoal and a least affinity for mammalian DHFR

9. Cotrimoxazole
• Sulfamethaxazole + Trimethoprim
• Fixed dose combination ( 5:1 ), eg: 400mg : 80 mg
• Rationale of combination:
– Both have Similar half lives (t½) – 11 hrs
– Combination is bactericidal, because of SEQUENTIAL
INHIBITION (but bacteriostatic when used alone)
– Combination has wider spectrum of antibacterial
activity
– Combination delays development of resistance
Continued on next slide

10. Cotrimoxazole (2)
Synergistic action :-
• Sequential inhibition – blockade of folic acid
synthesis at two sites in a sequence
• Antimicrobial spectrum
– Gram –ve bacilli (E.coli, Shigella, Salmonella,
H.influenza, V.cholerae, Proteus mirabilis)
but not Pseudomonas
– Moderate action – N.gonorrhoea & N.meningitidis
– Chlamydia trachomatis
– Toxoplasma gondii
Continued on next slide

11. Cotrimoxazole inhibits synthesis of bacterial
THFA at two steps in a sequence

12. Cotrimoxazole – uses
1. Urinary Tract Infection
2. Prostatitis (gets Concentrated in prostatic fluid)
3. Respiratory tract infections
4. Acute sinusitis, bronchitis, otitis media
5. Typhoid – As alternative to ciprofloxacin (1st choice)
6. Bacterial diarrhoeas & dysentry
7. Nocardiasis
8. Sexually transmitted diseases
– Chancroid – Haemophilus ducreyi
– Lymphogranuloma – Chlamydia
– Gonorrhoea – N.gonorrhoea
9. Pneumonia – (Pneumocystis carinii in AIDS pts)

13. Pyrimethamine
• Like trimethoprim, also blocks DHFR , but has
greater affinity against protozoal DHFR.

14. Uses of other sulfonamide combinations
• Sulfadiazine + Pyrimethamine
– Toxoplasmosis
• Sulfadoxine + Pyrimethamine
– CHLOROQUINE REISTANT FALCIPARUM MALARIA
– Both drugs has long half life (>95 hrs)
– 1500mg + 75mg (20:1 ratio)

15. Adverse effects - Sulfonamides
1. Crystalluria & Renal toxicity
– Less soluble in acidic urine & gets precipitated in
kidney & renal tubules
– Treating it:- ↑intake of water & make urine alkaline
2. Hypersensitivity reactions –
– Rashes (mucocutaneous junctions),
– Stevens –Johnson syndrome (erythema multiformae,
ulcerations of mucous membrane & genitalia)
– Eosinophilia
– Drug fever
Continued on next slide

16. 3. KERNICTERUS in neonates
– Sulfonamides displace bilirubin from protein binding
sites
– Since Blood Brain Barrier (BBB) in neonates not fully
developed, this free bilirubin crosses BBB and gets
deposited in basal ganglia & Subthalamic nuclei.
4. Haemolytic anaemia
– Genetic deficiency of G6PD
– Agranulocytosis, thrombocytopenia
– Megaloblastic anemia – on long term use
Adverse effects – Sulfonamides (2)

17. Drug interactions
• Sulfonamides increases activity of oral
anticoagulants, sulfonylureas & methotrexate
by displacing them from protein binding sites.

18. Other commonly used Sulfonamides
• Sulfasalazine
• Topical agents
– Sodium Sulfacetamide
– Silver Sulfadiazine
– Mefanide

19. Sulfasalazine
• Uses :- Ulcerative colitis, Rheumatoid arthritis
• Poorly absorbed in GIT
• Degraded by bacterial flora of colon to:
1) 5- Aminosalicylic acid (5-ASA) &
2) Sulfapyridine.
• 5-ASA is the anti-inflammatory agent in ulcerative
colitis (active component in Ulcerative colitis)
• Sulfapyridine serves as carrier moiety for 5-ASA
(active component in Rheumatoid arthritis)

20. Sodium sulfacetamide
• 10, 20 & 30 % ophthalmic solution or
ointment to treat
– Trachoma (Chlamydia trachomatis)
– Bacterial conjunctivitis
TOPICAL AGENT

21. Silver Sulfadiazine
• Least toxic topical sulfonamide ointment
• Preferred for prevention & treating infection
in burn cases.
• Active against large number of Gram -ve
bacteria including Pseudomonas.
• Additional antimicrobial action
– Slowly releases Ag+ ions
• Disadvantage – absorbed from abraded skin to
produce systemic side effects
TOPICAL AGENT

22. Mefanide
• Sulfonamide analogue
• Used topically
• Has both Gram + & -ve action
• Active even in presence of pus
• Effective against Pseudomonas & Clostridia
• Used in burn cases
TOPICAL AGENT

23. Bibliography
• K. D. Tripathi. “Essentials of Medical
Pharmacology” 7th Edition, Jaypee Brothers
Medical Publishers (P) LTD, New Delhi, India,
2013.
• Sharma HL, Sharma KK. “Principles
of Pharmacology” 2nd Edition, Paras Medical
Publishers, Hyderabad, India, 2012.