1. Sulfonamides, trimethoprim and QuinolonesBy
S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences

2. Antifolate drugs Sulfonamides Trimethoprim
Trimethoprim & Sulfamethoxazole mixture

3. Sulfonamides: chemistry

4. Sulfonamides: mechanism of action
Inhibition of dihydropetroate synthase

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

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

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

8. Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

9. 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

10. 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

11. Trimethoprim: chemistry

12. Trimethoprim: resistance
Reduced cell permeability
Overproduction of DHF reductase
Altered affinity of reductase

13. Trimethoprim: pharmacokinetics
Usually given orally alone or in combination with sulfamethoxazole
Mainly excreted into urine
More antibacterial activity in prostatic and vaginal fluids

14. 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

15. Adverse effects Megaloblastic anemia Leukopenia, granulocytopenia
Can be prevented by folinic acid
The AIDS patients have high frequency of unwanted reactions

16. DNA gyrase inhibitors
Fluoroquinolones
Nalidixic acid and cinoxacin

17. Fluoroquinolones: chemistry

18. Fluoroquinolones: chemistry-2

19. Fluoroquinolones: antibacterial activity
Block of bacterial DNA synthesis by
Inhibiting topoisomerase II, IV
Gram positive & negative bacteria
Mycoplasma & clamydia, legionella
Some mycobacteria
Anaerobic bacteria

20. Fluoroquinolones: resistance
Change in permeability
Loss of affinity

21. Fluoroquinolones: pharmacokinetics
Well absorbed after oral administration
Good distribution
Divalent cations impair absorption

22. Pharmacokinetic Properties of Fluoroquinolones

23. Fluoroquinolones: clinical uses
Urinary tract infection
Even with multi-drug resistant organisms
Bacterial diarrhea
Shigella, salmonella, toxigenic E. coli
Infections of soft tissues, bones and joints
Intra-abdominal and respiratory tract infections
Gonococcal infection
Chlamydial urethritis and cervicitis
Legionellosis
Tuberclusis and atypical mycobacterial infections

24. Fluoroquinolones: adverse effects
Nausea, vomiting & diarrhea
Headache, dizziness, insomnia, skin rash, abnormal liver test
Acute hepatitis & hepatic failure: trovafloxacin
Photosensivity: lomefloxacin, pefloxacin
QT prolongation: sparfloxacin
Hyperglycemia or hypoglycemia
May damage growing cartilage: arthropathy
Tendinitis

25. Nalidixic acid & cinoxacin
Excreted too rapidly
Useful for urinary tract infections