Pharmacology of Sulfonamides

1. Sulfonamides

4. • The first antimicrobial agent effective against pyogenic bacterial infections
PRONTOSIL RED
A dye used to treat experimental streptococcal
infections in mice
(Sulfonamido – chrysoidine)
Was found to be HIGHLY EFFECTIVE
Used to cure infants with staphylococcal
septicemias

5. Introduction
• In 1937: Prontosil was broken down in the body to release sulfanilimide
The active
antibacterial agent

6. • After this, a large number of synthetic sulfonamides were produced
• Bacteriostatic
• Extensively used in following years to come
HOWEVER
Use of sulfonamides became limited
Introduction
Rapid emergence of
BACTERIAL RESISTANCE
Availability of safe &
more effective drugs

7. *EXCEPTION
• COTRIMOXAZOLE – (Combination with Trimethoprim)
• Combination with Pyrimethamine (Malaria)
Introduction

8. Components:
• p-aminobenzene ring
• N1 substitution – solubility, potency and PK
property
• N4 free amino group – required for
antibacterial activity
Structure

9. Structure
*Structural Analogue of PABA*

10. Classification
The sulfonamides still of clinical interest
A. SHORT ACTING (4-8 HOURS) • Sulfadiazine
B. INTERMEDIATE ACTING (8-12 HOURS) • Sulfamethoxazole
C. LONG ACTING (~ 7 DAYS) • Sulfadoxine
• Sulfamethopyrazine
D. SPECIAL PURPOSE • Sulfacetamide sodium
• Silver sulfadiazine
• Sulfasalazine
• Mafenide
(Tripathi)

11. Cla
The s
ssification
ulfonamides still of clinical interest
A. Orally Absorbable
1. Short Acting (4-8 hrs) • Sulfadiazine
• Sulfacytine
• Sulfamethizole
• Sulfisoxazole
2. Intermediate Acting (8-12hrs) • Sulfamethoxazole
• Sulfamoxole
• Sulfadoxine
• Sulfamethopyrazine
3. Long Acting (~7 days)
B. Orally Non- Absorbable • Sulfasalazine
• Olsalazine
• Balsalazine
C. TopicalAgents • Silver sulfadiazine
• Mafenide
• Sulfacetamide sodium

14. Mechanism of Action
Leakage from Cell
Membrane
• Broadly put, sulfonamides
inhibit Nucleic Acid synthesis
• Specifically, sulfonamides
inhibit the synthesis of folates
in bacterial organisms

17. PTERIDINE PABA
+
TETRAHYDROFOLIC
ACID
DIHYDROPTEROIC ACID SYNTHASE
(Folic Acid Synthase)
DIHYDROPTEROIC
ACID
+ GLUTAMATE
DIHYDROFOLIC
ACID
DIHYDROFOLATE REDUCTASE
RNA DNA Proteins
FOLIC
ACID
DIHYDROFOLATE
REDUCTASE
(mammalian)
SULFONAMIDES =
B
a
c
t
e
r
i
a
M
a
n

18. Mechanism of Action
• Folic Acid is very essential for the growth of bacteria as it is crucial for nucleic
acid synthesis.
• Many bacteria synthesize their own folic acid from PABA
• Sulfonamides are structural analogues of PABA  enters the sequence in
place of PABA
• Sulfonamides compete for enzyme dihydropteroic acid synthase to create a
non-functional analogue of folic acid
• This is of no use to bacteria hence    GROWTH CEASES
(BACTERIOSTATIC ACTION)

19. Mechanism of Action
* Humans absorb folic acid directly from diet, hence sulfonamides are
SELECTIVELY TOXIC TO THE BACTERIA ONLY and not to the host cells!

20. • A – Rapidly and well absorbed orally
• D - Widely distributed in the body
- Crosses BBB and placenta
- Accumulates in prostatic fluid
- Extent of plasma protein binding differs  Longer acting agents are highly protein bound
• M – Acetylation in the Liver  acetylated metabolites are inactive but still contribute to S/E
Less soluble in ACIDIC URINE  Precipitation of CRYSTALLURIA  RENALTOXICITY
• E – Kidney by glomerular filtration
* More lipid soluble agents are highly reabsorbed  longer acting
Pharmacokinetics

21. Antibacterial Spectrum
• Primarily bacteriostatic
• Bactericidal concentrations can be attained in the URINE
• Effective against Gram positive + Gram negative bacteria

22. Antibacterial Spectrum
Sensitive Organisms
• S. pyogenes
• H. influenzae
• H. ducreyi
• C. granulomatis
• V. cholera
• Chlamydiae species
• Actinomyces
• Nocardia
• Toxoplasma
Resistant Organisms
• Gonococci
• Staphylococci
• Meningococci
• Streptococci
• E. coli
• Shigella
Mechanism of Resistance
• Due to mutations causing:
A. Overproduction of PABA
B. Altered nature of
dihydropteroic acid
synthetase
C. Loss of permeability of
sulfonamides through
bacterial membrane
D. Appearance of an
alternative pathway

23. Clinical Uses
A. Orally Absorbable Drugs
• Acute uncomplicated UTI
• Third Choice Drug
• Nocardiosis
• Chancroid (H. ducreyi)
• Lymphogranuloma (Chlamydia)
B. Oral Non-Absorbable Drugs
• Sulfasalazine is the drug of choice for ulcerative
colitis
• Sulfasalazine is also used in Rheumatoid Arthritis
Systemic use of sulfonamides ALONE is RARE now
C. Topical Agents
• Sodium sulfacetamide 
Ophthalmic solution/ointment
- Trachoma – Chlamydia
trachomatis
- Bacterial Conjunctivitis
• Silver sulfadiazine 
Least toxic, preferred over
mafenide
* Slowly releases silver ions 
additional antimicrobial action
- Prophylaxis/Infections in Burns
- Active against Pseudomonas

24. Adverse Effects
1. Crystalluria + Renal Toxicity
• Dose Related
Acetylated metabolites are less soluble in acidic urine
Precipitates in kidney and renal tubules
Causes crystalluria and renal obstruction
Risk can be minimized:
• Taking plenty of
fluids
• Alkalinizing urine

25. Adverse Effects
2. Hypersensitivity Reactions
• Rashes – especially at mucocutaneous junctions
• Steven’s Johnson’s Syndrome – erythema multiforme,
ulcerations of mucous membranes, malaise
• Eosinophelia
• Drug Fever
• Exfoliative dermatitis

26. Adverse Effects
3. Hemolysis
• Can occur in patients with G6PD deficiency
• Neutropenia, Agranulocytosis and thrombocytopenia can occur
4. Kernicterus in Neonates
• Can be precipitated especially in premature infants since their blood brain barrier is not
fully developed
SULFONAMIDES
Displaces bilirubin
from protein
binding site
Bilirubin passes
through BBB
Deposited in
Basal Ganglia +
Subthalamic
nuclei

27. Adverse Effects
5. Nausea, Vomiting, Epigastric Pain
6. Hepatitis

28. Cotrimoxazole

29. Introduction
(Cotrimoxazole)
• Introduced in 1969
• It is a RATIONAL fixed drug dose combination
• Sulfamethoxazole + Trimethoprim
• This combination is BACTERICIDAL
(Both drugs are bacteriostatic when given alone)

30. Trimethoprim vs. Sulfamethoxazole
(Cotrimoxazole)
TRIMETHOPRIM SULFAMETHOXAZOLE
• Diaminopyrimadine related to antimalarial drug • Intermediate acting PABA structural analogue
PYRIMETHAMINE
• MOA: Inhibits bacterial dihydrofolate • MOA: Inhibits folate synthase
reductase (DHFRase)
HUMAN FOLATE METABOLISM IS NOT INTERFERED WITH
• Bacteriostatic • Bacteriostatic
Combination is BACTERICIDAL against many organisms
• Pharmacokinetics:
A – More rapidly absorbed
D – 40% plasma protein bound
M – Partly metabolized in Liver
E – Excreted in urine
• Pharmacokinetics:
A – Rapidly absorbed
D – 65% plasma protein bound
M – Acetylation in Liver
E – Renal excretion by glomerular filtration

31. Rationale
(Cotrimoxazole)
• Both compounds have a similar half life (~10 hours)
• Two bacteriostatic drugs produces bactericidal action when combined
• The combination has a wider antibacterial spectrum
• The combination delays the development of bacterial resistance
• The MIC of each component can be reduced 3-6 times
• Trimethoprim enters many tissues and has a larger volume of distribution

32. Mechanism of Action
(Cotrimoxazole)
• Cotrimoxazole inhibits Nucleic Acid Synthesis by…
• …. causing SEQUENTIAL BLOCKADE of Folic Acid Synthesis in bacterial organisms

33. PTERIDINE PABA
+
TETRAHYDROFOLIC
ACID
DIHYDROPTEROIC ACID SYNTHETASE
(Folic Acid Synthase)
RNA DNA Proteins
FOLIC
ACID
DIHYDROFOLATE
REDUCTASE
(mammalian)
SULFAMETHOXAZOLE =
B
a
c
t
e
r
i
a
M
a
n
DIHYDROPTEROIC
ACID
+ GLUTAMATE
DIHYDROFOLIC
ACID
TRIMETHOPRIM = DIHYDROFOLATE REDUCTASE

34. Spectrum of Action
(Cotrimoxazole)
• All organisms sensitive for sulfonamides
• Additional organisms: S. typhi, Klebsiella, P.jiroveci
Sulfonamide resistant strains
• Mechanism of Resistance: Resistance to Trimethoprim is mostly through plasmid
mediated acquisition of DHFRase
*Resistance to the combination is slow to develop compared to the drugs alone!

35. Uses
(Cotrimoxazole)
 1 tablet twice daily X 3-10 days
• Acute Cystitis  Single dose therapy with 4 tablets
• Prostatitis
• Acute  1 tablet twice daily X 3 weeks
• Chronic  1 tablet twice daily X 6-12 weeks
* If patient is allergic to sulfonamides, trimethoprim can be given alone
*Cotrimoxazole is still used now… however, its popularity has decreased in the treatment
of systemic infections
1. Urinary Tract Infections
• Acute uncomplicated infections respond rapidly

36. Uses
(Cotrimoxazole)
2. Respiratory Tract Infections
Especially infections caused by Gram positive cocci and
Hemophilus species
• URTI + LRTI
• Chronic Bronchitis
• Sinusitis
• Otitis Media
 One DS tablet twice a day

37. Uses
(Cotrimoxazole)
3. Bacterial Diarrheas + Dysentery
E. coli, Shigella, non-typhoid Salmonella, Yersinia
• Acute gastroenteritis
• Traveller’s Diarrhea
• Cholera
 One DS tablet twice a day X 7 days
* Fluourquinolones are the drugs of choice, however Cotrimoxazole is a valuable
alternative

38. Uses
(Cotrimoxazole)
4. Pneumocystis jiroveci (Pneumonia in Neutropenic/AIDS patient)
• High doses Cotrimoxazole is prophylactic as well as therapeutic
• Drug of choice for pneumonia due to P. jiroveci
Treatment  One DS tablet four times a day X 2-3 weeks
Prophylaxis  One DS tablet daily
* Adverse effects necessitates discontinuation in 20% cases

39. Uses
(Cotrimoxazole)
5. Sexually transmitted Diseases
• Chancroid – Cotrimoxazole is the 3rd choicedrug
 One DS tablet twice daily X 14 days
• Non-specific urethritis
• Lymphogranuloma
• Gonorrhea

40. Uses
(Cotrimoxazole)
6. Nocardiosis
• Drug of choice for pulmonary lesions/brain abscesses due to Nocardia
7. Typhoid
• Was initially effective and an alternate drug for typhoid. Now it is unreliable and
seldomly used
8. Melioidosis

41. Intravenous
(Cotrimoxazole)
• IV Cotrimoxazole in 5% Dextrose is preferred to treat
• moderate to severe P.jirovecipneumonia
• Shigellosis
• typhoid fever
• nocardiosis
• septicemia

42. Adverse Effects
(Cotrimoxazole)
• All the adverse effects seen with Sulfonamides can be seen with Cotrimoxazole
• Nausea, Vomiting, Headache, Stomatitis
• Rashes
• Folate deficiency ONLY in patients with marginal folate levels
• Blood dyscrasias (RARE)

43. Contraindications
(Cotrimoxazole)
• AVOID IN PREGNANCY
• Trimethoprim is an antifolate  Theoretical teratogenic risk
• Given near term  methemoglobinemia and neonatal hemolysis
• Uremia in renal disease
• Greater risk of bone marrow toxicity in the elderly
• Fever, Rash and bone marrow hypoplasia among AIDS patients with P.jiroveciinfection

44. Interactions
(Cotrimoxazole)
• Diuretics + Cotrimoxazole  Higher incidence of THROMBOCYTOPENIA

45. Recent Advances
(Ictaprim)
• Ictaprim
• Recently introduced in August 2008
• Trimethoprim analogue
• ROA: IV
• More effective and better tolerated than Trimethoprim
• Equally effective as Linezolid in MRSA skin and soft tissue infections
• Highly active against VRSA
*Phase III trials are being conducted to explore whether the same efficacy is
retained if administered orally

46. Sulfadoxine + Pyrimethamine

47. Introduction
(Sulfadoxine + Pyrimethamine)
• It is a RATIONAL fixed drug dose combination
• Synergistic
• Sulfadoxine + Pyrimethamine

48. Rationale
(Sulfadoxine + Pyrimethamine)
• Both drugs have ultra long plasma half life (> 95 hrs)
• Acts faster in combination
• Curative for Chloroquine resistant P.falciparum malaria
• Toxoplasmosis

49. Mechanism of Action
(Sulfadoxine + Pyrimethamine)
• Sequential Block in protozoal folic acid synthesis
*Pyrimethamine blocks dihydrofolate reductase but has greater activity against protozoal
dihydrofolate reductase
*Pyrimethamine unfortunately has some activity against mammalian dihydrofolate
reductase
- Administer folinic acid (Citrovorum factor) during therapy

50. Adverse Effects
(Sulfadoxine + Pyrimethamine)
• Serious cutaneous reactions