1. Sulfonamides صيدلانية نظري / د . فارس رابع صيدلة 23 / 4 / 2016
4th Year Pharmacy
2016

2. Antifolate drugs Sulfonamides Trimethoprim
Trimethoprim & Sulfamethoxazole mixture

3. Lead Compound Notes Prontosil - red dye
Antibacterial activity in vivo (1935)
Inactive in vitro
Metabolised to active sulfonamide
Acts as a prodrug
Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections

4. Sulfonamides: mechanism of action
Inhibition of dihydropetroate synthase

5. Mechanism of action para-Aminobenzoic acid Dihydropteroate synthetase
Sulfonamides
Reversible
inhibition _
Dihydrofolate
L-Glutamic acid
Dihydrofolate
reductase
NADPH
Tetrahydrofolate
(coenzyme F)
Trimethoprim _

6. Mechanism of action Binding interactions Active site Active site O C H2 N S O N R H 2
Ionic bond
H-Bond
van der Waals
interactions

7. Synthesis of Sulfa drugs

8. Sulfonamides - Drug Metabolism
Sulfathiazole
Insoluble metabolite
N-Acetylation
Notes
Sulfonamides are metabolised by N-acetylation
N-Acetylation increases hydrophobic character
Reduces aqueous solubility
May lead to toxic side effects

9. Structure-Activity Relationships
Aromatic
para-Amino group
Sulfonamide
para-Amino group is essential (R1=H)
para-Amido groups (R1=acyl) are allowed
inactive in vitro, but active in vivo
act as prodrugs
Aromatic ring is essential
para-Substitution is essential
Sulfonamide group is essential
Sulfonamide nitrogen must be primary or secondary
R2 can be varied

10. Sulfonamides: antimicrobial activity
Gram positive and negative bacteria
Nocardia, chlamydia trachomatis
Some protoza
Some enteric bacteria
Rickettisiae stimulated!

11. Sulfonamides: resistance
Overproduction of PABA
Low affinity dihydropetroate synthase
Loss of permeability to sulfonamides

12. Sulfonamides: pharmacokinetics
Oral absorbable
Short
Medium
Long
Oral, nonabsorbable
topical
Serum protein bind
20 ~ 90%
Excreted into urine

13. Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

14. Sulfonamides: chemistry

15. Sulfonamides: clinical uses
Oral absorbable agents
Sulfisoxazole, sulfamethoxazole
To treat urinary tract infection
Sulfadiazine: toxoplasmosis
Sulfadoxine: long acting, in a combination for treatment of malaria
Oral nonabsorbable agents
Ulcerative colitis, enteritis, other inflammatory bowel disease
Topical agents
Sulfacetamide: ophthalemic
Mafenide & silver sulfadiazine: topically ( Burn )

16. Sulfonamides: adverse reactions
Cross allergenic sulfonamide drugs:
Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic agents, and others
Fever, skin rashes, exfoliative dermatitis,photosensivity, urticaria, nausea, vomiting, diarrhea
Stevens-Johnson syndrom
Urinary tract disturbances
Crystalluria, hemturia, obstruction
Hematopoietic disturbance
Hemolytic or aplastic anemia
Granulocytopenia, thrombocytopenia, leukmoid reaction
Hemolysis in G-6PDH deficient patients
Kernicterus in newborn of mothers have taken near the end of pergnancy

17. Trimethoprim: chemistry

19. Clinical use Oral trimethoprim Oral trimethoprim-sulfamethoxazole
Acute urinary infection
Oral trimethoprim-sulfamethoxazole
P jiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract infection,
Active against many respiratory pathogens
Intravenous trimethoprim-sulfamethoxazole
Gram negative sepsis, pneumocystis pneumonia
Shigllosis, typhoid fever
Oral pryrimethamine with sulfanamide
With sulfadiazine in Leishmaniasis, toxoplasmosis
With sulfadoxine in malaria

20. Adverse effects Sulfones ( Dapson)
Megaloblastic anemia
Leukopenia, granulocytopenia
Can be prevented by folinic acid
The AIDS patients have high frequency of unwanted reactions
Sulfones ( Dapson)
Thought to inhibit dihydropteroate synthetase
Used in the treatment of leprosy