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1. SULPHONAMIDES AND CO
TRIMOXAZOLE : A BRIEF OUTLOOK
BY : VISHNU. R. NAIR
THIRD YEAR PHARM.D
NATIONAL COLLEGE OF PHARMACY
KERALA UNIVERSITY OF HEALTH SCIENCES (KUHS),
KERALA STATE

2. SULPHONAMID
ES

3. A. GENERAL FEATURES:
• Defined as “SULFA-related group of antibiotics, that are derived
from sulphanilamide, which are able to prevent the multiplication
of some pathogenic bacteria”……………………..
• Mainly, they are derivatives of PRONTOSIL RED (A dye)
• Inactive in nature
• Becomes active in-vivo……………………..

4. B. CLASSIFICATION OF SULPHONAMIDES:
• BASED ON SITE OF ACTION:
1. For general infections:
- Sulphanilamide - Sulphadiazine - Sulphamethoxazole
- Sulphadoxine - Sulphapyridine - Sulphamethocine
- Sulphathiazole
2. For intestinal infections:
- Pthalyl Sulphathiazole
- Succinyl Sulphathiazole
- Sulphasalazine
3. For Dermatitis:
- Dapsone - Solapsone

5. CONTINUED…………………………….
4. For local infections:
- Sulphacetamide sodium
- Mafenide sodium
- Silver Sulphadiazine
5. For UTI (Urinary Tract Infections):
- Sulphadiazine
- Sulphacetamide sodium
• BASED ON PHARMACOKINETIC PROPERTIES:
1. Poorly acting Sulphonamides :
- Sulphasalazine
- Pthalyl sulphathiazole

6. CONTINUED……………………………..
2. Rapidly absorbed and excreted Sulphonamides ( Systemic Sulphonamides):
- Sulphamethoxazole
- Sulphisoxazole (Sulphafurazole)
3. Topically used sulphonamides:
- Mafenide sodium
- Sulphacetamide sodium
- Silver Sulphadiazine
• BASED ON CHEMISTRY:
1. N4-substituted sulphonamides (PRO-DRUGS):
- Prontosil dye
- sulphaguanidine

7. CONTINUED……………………………..
2. N1-substituted sulphonamides:
- Sulphadiazine
- Sulphacetamide
- Sulphadimidine
3. Both N1 and N4 substituted sulphonamides:
- Succinyl Sulphathiazole
- Pthalyl Sulphathiazole
4. Non-aniline sulphonamides:
- Mafenide sodium

8. CONTINUED………………………………
• BASED ON PHARMACOLOGICAL ACTIVITY:
1. Anti-bacterial agents:
- Sulphasalazine
- Sulphisoxazole, etc.
2. Oral hypoglycemic agents:
- Tolbutamide
3. Diuretics:
- Furosemide - Bumetanide - Chlorthalidone
4. For Dermatitis:
- Dapsone - Solapsone

9. CONTINUED………………………………….
• BASED ON DURATION OF ACTION:
1. Ultra-long acting ones (half-life : >50 hours) :
- Sulphasalazine - Sulphacetamide sodium - Sulphalene
- Sulphadoxine
2. Long-acting ones (half-life >24 hours):
- Sulphadimethoxine
3. Intermediate acting ones: (half-life : 10-24 hours):
- Sulphamethoxazole
4. Short acting ones (half-life < 10 hours):
- Sulphamethizole - Sulphisoxazole……………………………..

10. C. STRUCTURE-ACTIVITY RELATIONSHIP OF SULPHONAMIDES
(SAR):
• Sulphonamides are considered to be the derivatives of SULPHANILAMIDES (para-amino benzene
sulphonamide)
• Individual compounds of sulpha drugs differ on the basis of N1-substitution, which imparts solubility
and potency to the drug
• Free amino (NH2-) group is essential for anti-bacterial activity
• Sulphanilamide skeleton is the minimum structure required for anti-bacterial activity
• Sulphur atom should be directly linked to the benzene ring
• Amino and sulphonyl radicals should be at 1,4- position
• 1,2 and 1,3 isomers are less active
• Any substitution on aromatic ring/ replacement of benzene ring by other ring decreased/ abolished
activity of the drug

11. CONTINUED……………………………..
• Substitution of heterocyclic aromatic nucleus in N1-position yields highly potent
compounds
• N1-disubstitution renders compound ineffective (since at least 1 hydrogen is necessary for
ionization, to show anti-bacterial activity)
• pKa value should be in between 6.6-7.4 for exhibiting anti-bacterial activity
• Lipid solubility is proportional to the pharmacokinetic and anti-bacterial activity of the drug
• Lipid solubility is directly proportional to half life of the drug…………………

12. D. MECHANISM OF ACTION OF SULPHONAMIDES:
• UNDER NORMAL CONDITIONS (IN BACTERIA):
PTERIDINE combines with PABA (PARA-AMINO BENZOIC ACID) in the presence of
enzyme DIHYDROPTEROATE SYNTHETASE  Forms DIHYDROPTEROIC ACID (a)
GLUTAMATE gets added to (a)  forms DHFA (DIHYDRO FOLIC ACID) DHFA, in the
presence of DIHYDROFOLATE REDUCTASE enzyme gets converted to THFA
(TETRAHYDROFOLIC ACID) THFA forms THYMIDYLIC ACID  DNA and genetic
bases (purine, pyrimidine, thymidine etc. ) formed…………………….
SULPHONAMIDES  block the enzyme DIHYDROPTEROATE SYNTHETASE  thus
PTERIDINE cannot combine with PABA  Thus Dihydropteroic acid is not
formed……………..

13. CONTINUED………………………………..
• Sulphonamides are bacteriostatic in nature
• Thus, their anti-bacterial efficacy is just 20-30%
• Thus, they are used in combination with TRIMETHOPRIM (Di-amino pyrimidine) as
COTRIMOXAZOLE (SULPHAMETHOXAZOLE+TRIMETHOPRIM
COMBINATION)…………………………………………………

14. E. ANTI-BACTERIAL SPECTRUM OF SULPHONAMIDES:
• Sulphonamides are primarily BACTERIOSTATIC against Gram positive and Gram negative
organisms
• Organisms that are sensitive to sulphonamides include:
- Streptococcus pyogenes - Calymmobacterium granulomatis
- Haemophilus influenzae - Vibrio cholera
- Staphylococcus aureus - Meningococci
- E.coli - Toxoplasma
- Shigella
- Actinomyces………………………………….

15. VI. SULPHONAMIDE RESISTANCE:
• Organisms that are resistant to sulphonamides include:
- Staphylococcus aureus - E.Coli
- Meningococci - Streptococcus viridans
- Gonococci - Anaerobes
• Mechanisms of resistance include:
1. Production of increased amounts of PABA
2. Mutants  contain folate synthase enzyme  shows less affinity for sulphonamides
3. Bacteria adopt alternative pathway for folate metabolism
* Usually CROSS RESISTANCE is observed for microbes within sulphonamides…………….

16. VII. PHARMACOKINETICS:
• Rapidly and completely absorbed from GIT
• Extent of protein binding : 10-95%
• Widely distributed in body
• Enters serous cavities easily
• Cross placenta easily
• Metabolized in liver by non-microsomal acetyl transferase
• Excreted by kidney (via GLOMERULAR FILTRATION)………………………..

17. VIII. ADVERSE DRUG REACTIONS OF SULPHONAMIDES:
• Nausea
• Vomiting
• Epigastric pain
• Crystalluria
• Hypersensitivity reactions:
- Urticaria
- Drug fever
- Rashes
• Photosensitivity
• Stevens-Johnson syndrome
• Kernicterus………………………………….

18. IX. DRUG INTERACTIONS OF SULPHONAMIDES:
1. SULPHONAMIDES + WARFARIN Decreased metabolism of WARFARIN
2. SULPHONAMIDES + PHENYTOIN Increased levels of PHENYTOIN
3. SULPHONAMIDES + METHOTREXATE Increased levels of METHOTREXATE
METHOTREXATE TOXICITY
4. SULPHONAMIDES + KETOROLAC  Increased toxicity of each other life-
threatening condition may occur
5. SULPHASALAZINE + AMILORIDE  Increased Serum potassium levels
HYPERKALEMIA Serious interaction………………………..

19. X. CONTRAINDICATIONS FOR SULPHONAMIDES:
• Blood dyscrasias
• Don’t use in Glucose-6-phosphate dehydrogenase individuals hemolysis can occur
• Hypersensitivity
• Intestinal or urinary tract obstruction
• Porphyrias
• Vitamin.K deficiency
• Thyrotoxicosis ……………………………..

20. XI. INDIVIDUAL COMPOUNDS:
•SULPHADIAZINE:
- Protein binding capacity : 50%
- Acetylated derivative of drug less soluble in urine  Crystalluria can occur
- Drug cross BBB easily thus used for MENINGITIS (previously)
- Dose : 0.5 g BID…………….

21. CONTINUED………………………………….
•SULPHADOXINE, SULPHAMETHOPYRAZINE:
- Ultra-long acting compounds (Due to increased plasma protein binding, and slow renal
excretion)
- Half-life: 5-9 days
- Uses:
a. Above drugs + PYRIMETHAMINE  treatment of PLASMODIUM FALCIPARUM
associated malaria
b. PNEUMOCYSTIS JIROVECI PNEUMONIA in AIDS patients
c. TOXOPLASMOSIS
- ADRs: serious cutaneous reactions  thus not much used……………………….

22. CONTINUED………………………………
•SULPHAMETHOXAZOLE:
- Slow oral absorption
- Slow urinary excretion
- Preferred compound to be combined with TRIMETHOPRIM, since both have similar half-
lives (10 hours)
- ADR: Crystalluria
- Dose:
1 g BID for 2 days  then 0.5 g BID………………………..

23. CONTINUED…………………………………….
•SULPHACETAMIDE SODIUM:
- Mainly used in the treatment of CHLAMYDIAL INFECTIONS ….example OPHTHALMIA
NEONATORUM caused by CHLAMYDIA OCULOGENITALIS
- ADR: Sensitivity reactions
- DOSE: 10%. 20% 30% eye drops…………………….

24. CONTINUED………………………………………..
•MAFENIDE SODIUM:
- Mainly used topically
- Inhibits Gram positive and Gram negative bacteriae
- Mainly active in the pus presence (contrary to normal sulphonamides, which becomes
inactive in the presence of pus), and against PSEUDOMONAS and CLOSTRIDIA, that are
not inhibited by normal sulphonamides
- ADR:
1. Burning sensation and severe pain at raw site 3. Hyperventilation
2. Acidosis 4. Rashes
- DOSE: 1% Topical cream……………………………..

25. CONTINUED……………………………………
•SILVER SULPHADIAZINE:
- Active against most bacteria and fungi
- Anti-microbial action is attributed to slow release of SILVER ions…
- USES:
1. Preventing infection of burnt surfaces
2. Chronic ulcers
- ADR:
1. Itching
2. Burning sensation
- DOSE: 1% cream……………………………….

26. CONTINUED…………………………………
•SULPHASALAZINE:
- USES:
1. Ulcerative colitis
2. Rheumatoid arthritis
- DOSE: 1-2 g QID
- ADRs:
1. Anorexia
2. Headache……………………………………………

27. CONTINUED………………………………………
•DDS (DAPSONE, DIAMINO-DIPHENYL SULFONE):
- USES:
1. Leprosy
2. Nocardiosis
- DOSE: 100 mg daily
- ADRs:
1. Peripheral neuropathy
2. Anemia…………………………

28. CO-TRIMOXAZOLE

29. A. GENERAL FEATURES:
• It is a combination of TRIMETHOPRIM (1 part) + SULPHAMETHOXAZOLE ( 5 parts)
• SULPHAMETHOXAZOLE is selected for combination with TRIMETHOPRIM, since both
possess nearly the same half-life (10 hours)
• SULPHAMETHOXAZOLE Possesses poor volume of distribution compared to
TRIMETHOPRIM thus we use 5 times volume of SULPHAMETHOXAZOLE compared
to TRIMETHOPRIM
• Individually SULPHAMETHOXAZOLE acts as BACTERIOSTATIC when combined
with TRIMETHOPRIM becomes BACTERICIDAL
• TRIMETHOPRIM is not a sulfa drug, but it possess a DIAMINO-PYRIMIDINE ring in its
structure, which is closely related to the anti-malarial drug PYRIMETHAMINE
• TRIMETHOPRIM blocks DIHYDROFOLATE REDUCTASE enzyme  favors
SULPHAMETHOXAZOLE to become BACTERICIDAL………………………….

30. B. SPECTRUM OF ACTIVITY OF CO-TRIMOXAZOLE:
• Organisms covered include:
1. Salmonella typhi
2. Enterobacter
3. Klebsiella species
4. Staphylococcus aureus
5. Streptococcus pyogenes
6. Shigella
7. E.Coli
8. Pneumocystis jiroveci
9. Haemophilus influenzae……………………

31. C. RESISTANCE TO CO- TRIMOXAZOLE:
• Organisms develop resistance to CO-TRIMOAZOLE mainly through:
1. Plasmid-mediated acquisition of DHFRase (DIHYDROFOLATE REDUCTASE)
Possess lower affinity for inhibitor
* Mainly such kind of resistance is observed in widespread use…………………………

32. D. ADR OF CO- TRIMOXAZOLE:
• Nausea
• Vomiting
• Rashes
• Megaloblastic anemia (in folate deficient patients)
• Headache
• Toxic epidermal necrolysis
• Erythema multiforme
• Peripheral neuritis
• Stevens- Johnson syndrome
• Hyperkalemia …………………………………………….

33. E. CONTRAINDICATIONS OF CO- TRIMOXAZOLE:
• Documented hypersensitivity
• Pregnancy: May cause NEONATAL HEMOLYSIS and METHAEMOGLOBINEMIA
• Elderly: May increase risk of BONE MARROW TOXICITY
• Patients with renal disease: Increased risk of HYPERKALEMIA and UREMIA can occur
• Increased dose given to AIDS patients with PNEUMOCYSTIS JIROVECI infection
can cause BONE MARROW HYPERPLASIA
• In MEGALOBLASTIC ANEMIA patients
• In patients with significant degree of HEPATIC IMPAIRMENT…………..

34. F. DRUG INTERACTION OF CO-TRIMOXAZOLE:
• CO- TRIMOXAZOLE + DIURETICS THROMBOCYTOPENIA risk
• CO-TRIMOXAZOLE + AMIODARONE  increased QT-interval High life-threatening
risk
• CO- TRIMOXAZOLE + BIVALIRUDIN  Increased levels of BIVALIRUDIN
• CO-TRIMOXAZOLE + CYCLOSPORINE  Increased risk of NEPHROTOXICITY
• CO –TRIMOXAZOLE + ARGATROBAN  Increased levels of
ARGATROBAN…………………………..

35. G. DOSE OF CO- TRIMOXAZOLE:
•20 mg (TRIMETHOPRIM) + 100 mg (SULPHAMETHOXAZOLE)
: PAEDIATRIC TABLET
•160 mg (TRIMETHOPRIM) + 800 mg
(SULPHAMETHOXAZOLE): For ADULTS,
BID………………………….

36. H. USES OF CO- TRIMOXAZOLE:
• In UTI (URINARY TRACT INFECTION):
- For CHRONIC CYSTITIS
- For CHRONIC PROSTATIS
• In RESPIRATORY TRACT INFECTIONS:
- For FACIO-MAXILLARY INFECTIONS
- For OTITIS MEDIA
- For CHRONIC BRONCHITIS
• In BACTERIAL DIARRHOEAS and DYSENTRY
• In PNEUMOCYSTIS JIROVECI associated PNEUMONIA:
- Both PROPHYLACTIC and THERAPEUTIC value in AIDS patients

37. CONTINUED……………………….
• In CHANCROID:
- 3rd line drug of choice
- Less expensive
- Alternative to CEFTRIAXONE, AZITHROMYCIN or CIPROFLOXACIN
• To protect AGRANULOCYTOSIS patients from RESPIRATORY TRACT INFECTIONS
• In SEPTICAEMIAS ( Intensive parenteral therapy)…………………………………

38. COTRIMAZINE (GENERAL INFO. ONLY):
• Combination of TRIMETHOPRIM and SULPHADIAZINE
• Have similar properties and uses as that of CO-TRIMOXAZOLE
• DOSE:
-90 mg (TRIMETHOPRIM) + 450 mg (SULPHADIAZINE) tablet
-180 mg (TRIMETHOPRIM) + 820 mg (SULPHADIAZINE) tablet…………………

39. QUERIES ??????

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