1. Antimicrobials - Sulfonamides Antimicrobials - Sulfonamides Pharmacology -1 DSX 215 DSX 215 Dr/ Abdulaziz Saeedan Pharmacy College Pharmacy College 1

2. Sulfonamides - Chemistry  Sulfonamides are synthetic drugs having antibacterial activity.  Sulfonamides are derivatives of Sulfanilamide, which is similar chemically to para aminobenzoic acid (PABA). ► So, all Sulfonamides are similar chemically to PABA.  Sulfonamides contains: 1- Sulfonamido group (SO2 -NH2). 2- Free amino group (NH2) at the para position. ► The free amino group is required for the antibacterial activity of sulfonamides. 2

3. Action & Spectrum  Pharmacological Action: bacteriostatic Sulfonamides acts as bacteriostatic  Antimicrobial Spectrum : Sulfonamides have broad spectrum activity against gram- positive and gram-negative bacteria.  Gram positive: 1- Cocci: ► Staphylococci, Streptococci, Pneumococci, Meningococci 2- Bacilli: ► Corynebacterium, Clostridium  Gram negative:  Gram negative: ► Salmonella, E. coli  Sulfonamides are NOT effective against viruses and fungi 3

4. Importance of PABA dihydropteroate synthetase  PABA is utilized by bacteria and converted by dihydropteroate synthetase enzyme into dihydrofolic acid (1 st step). dihydrofolate reductase  Dihydrofolic acid converted by dihydrofolate reductase enzyme into tetrahydrofolic acid (2 nd step), then to purines which are essential for synthesis of nucleic acids (DNA) of bacterial cell. ► In absence of DNA molecules, the bacterial cell cannot divide. 4

5. MOA of Sulfonamides Due to the chemical similarity between sulfonamides and PABA, bacteria utilize sulfonamides instead of PABA, so prevent the synthesis of dihydrofolic acid (1 st step) and block the synthesis of DNA of bacterial cell, then multiplication of bacteria is stopped. This means that sulfonamides act as bacteriostatic agents 5

6. NOTE: Sulfa drugs do not cause the same effect in mammalian cells, because mammalian cells do not synthesize folic acid. ► Folic acid is a dietary requirement. ► So we need to consume folic acid. 6

7. Sulfonamides / Trimethoprim combination ( Sulfonamides / Trimethoprim combination ( co-trimoxazole)  Ex: Combination of sulfamethoxazole and trimethoprim, in the ratio of 5 : 1.  The combination is usually a bactericide agent.  MOA: dihydropteroate synthetase 1- Sulfonamides inhibits dihydropteroate synthetase (1 st Step). dihydrofolate reductase 2- Trimethoprim inhibits dihydrofolate reductase (2 nd Step). 3- Inhibition of these 2 enzymes interferes with 2 successive steps in folic acid synthesis, So inhibits synthesis of nucleic acids. 7

8. Pharmacokinetics Sulfonamides are mainly given orally 1)Oral absorbable sulfonamides: The main site of absorption is small intestine. After absorption, a part of sulfonamides binds to plasma proteins. This binding may be: This binding may be: a- Firmly: In this case, sulfonamides are released slowly from plasma proteins producing prolonged duration of action. ► Long acting sulfonamides. b- Loosely: In this case, sulfonamides are released rapidly from plasma proteins producing short duration of action. ► Short acting sulfonamides. 8

9. Pharmacokinetics (cont.) Sulfonamides are widely distributed in the body. ► They can pass through most barriers as BBB and placental barrier. acetylation oxidation Sulfonamides are metabolized mainly in the liver by acetylation and oxidation. ► The acetylated product of sulfonamides is inactive and precipitated in acid urine forming crystalluria. ► The oxidative product of sulfonamides is inactive and is responsible for photosensitization. Sulfonamides are eliminated in the urine, partly as such and partly as acetylated derivative. ► Rate of excretion increases in alkaline urine. 2) Oral non-absorbable sulfonamides Ex: Sulfasalazine, Sulfaguanidine 3) Topical: Ex: Sulfacetamide, silver sulfadiazine. 9

10. Sulfonamides- Classes I. Topical  Sulfacetamide  Silver sulfadiazine  Mafenide acetate (sulfamylon cream ) II. Intestinal  Sulfasalazine  Sulfaguanidine  Sulfathiazole 10

11. Sulfonamides- Classes a. Short acting  Sulfadiazine  Sulfadimidine  Sulfafurazole III. Systemic b. Intermediate acting  Sulfamethoxazole c. Long acting  Sulfamethoxine  Sulfadimethoxine  Sulfamethoxypyridazine  Sulfamethopyrazine 11

12. CLINICAL USES  The use of sulfonamides is limited to few infections due to: ► Development of resistance ► Availability of more safer and more effective antimicrobial agents  In general Sulfonamides are rarely used as single agents. ► They are used in combination with trimethoprim and pyrimethamine. 12

13. CLINICAL USES (cont.) A. Topical: 1. Ocular infections ► Sulfacetamide eye drops 10- 30% 2. Infected burns ► Mafenide acetate (sulfamylon cream ) ► Silver sulfadiazine B- Intestinal: Sulfasalazine is used for treatment of: B- Intestinal: ► Sulfasalazine is used for treatment of:  Ulcerative colitis - Bacterial diarrhoea - Enteritis and dysentery. C. Systemic:  Tonsillitis, prophylaxis of rheumatic fever.  Respiratory tract infection such as chronic bronchitis.  Urinary tract infection such as acute cystitis.  Treatment of typhoid. 13

14. Adverse Reactions  The common side effects are: 1- Nausea and vomiting. 2- Allergic symptoms including skin rash, urticaria. ► So, sulfonamides are prescribed carefully. 3- Urinary tract problems following precipitation of Sulfonamides in acidic urine. ► Crystalluria, hematuria, renal colic, renal obstruction. 4- Photosensitization reactions.  The uncommon allergic reactions include: 1- Acute toxic hepatitis. 2- Intravascular haemolysis in patients with glucose- 6-phosphate dehydrogenase deficiency. 14

15. NOTES: When sulfonamide is used systemically: 1. The liver functions must be checked carefully. 2. The patient must be given sufficient amount of water (3 - 4 L of water/day) to produce 1.2 L/day of urine. 3. Urinary alkalinizerCONTRAINDICATIONS 1. Pregnancy 2. Nursing mother 3. Infants under 6 weeks 4. Renal or hepatic failure 15

16. Thank you 16