1. First effective chemotherapeutic agent
SULFONAMIDES
First effective chemotherapeutic agent

2. Chemistry Structural analogue of PABA.
Sulfonamides are with diff. chemical, physical, pharmacological and anti bacterial properties.
Produced by substitutions at gp (-SO2 –NH –R) or the amide group (-NH2) of sulfanilamide nucleus.
Sulfanilamide is para-aminobenzenesulfonamide

4. CLASSIFICATION
Well absorbed by Mouth and Rapidly eliminated (short Acting)
a. General Purpose
Sulfadiazine
b. Mainly for UTI
Sulfisoxazole
Sulphamethizole
Sulfamethoxazole

5. Well absorbed by GIT and Slowly eliminated (Long Acting)
Sulphadoxine
Sulphamethoxypyridazine
Sulphadimethoxine
Sulphaphenazole
Poorly absorbed by GIT
Sulfasalazine

6. For Topical Application
Sulfacetamide
Silver Sulfadiazine
Mafenide
Miscellaneous Group
Sulfapyridine
Sulfonamide Combination
Cotrimoxazole (Sulfamethoxazole & trimethoprim)
Fansidar (Sulfadoxine & Pyrimethamine)

7. PHARMACOKINETICS
Mostly well absorbed after oral adm. Divided into three major groups.
Oral absorbable
Oral non absorbable
Topical

8. Oral absorbable absorption – stomach and intestine
Distribution – Widely distributed
CNS, CSF, placenta and fetus
PPB 20 – 90 % to serum albumin
PPL 2 – 6 hrs
Metabolism – Liver
Excretion – Urine , feces, bile, milk and other secretions

9. Metabolism
A portion of the absorbed drug is acetylated or glucronidated in the liver.
Dosage reduction is required in renal failure.

10. MOA X X They are bacteriostatic PABA Sulfonamides
Dihydropteroate Synthase
Sulfonamides
Dihydrofolic Acid (Folate) X
Dihydrofolate Reductase
Trimethoprim
Tetrahydrofolic Acid
Purines
DNA

11. Sulfonamides susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA.

12. ANTIBACTERIAL SPECTRUM
Exert bacteriostatic effect
Gram +ve and Gram -ve bacteria
Some enteric bacteria like E. Coli, Shigella, Salmonella, Klebsiella.
Nocardia, Chlamydia trachomatis and some protozoa.

13. Resistance
Mammalian cells lack the enzymes required for folate synthesis from PABA and depend on exogenous source of folate, so they are not susceptible to sulfonamides.

14. Resistance in bacteria
Sulfonamides resistance may occur as a result of mutations.
A- Overproduction of PABA
B- Production of a folic acid synthesizing enzyme that has low affinity for sulfonamides.
C- Impair permeability to the sulfonamide or active efflux
An alternative metabolic pathway for synthesis of essential metabolite

15. Therapeutic Uses A- Oral Absorbable Agents Urinary Tract Infections
Not therapy of first choice
Sulfadiazine with pyrimeythamine---acute toxoplasmosis
B- Oral Nonabsorbable Agents
Sulfasalazine is used in ulcerative collitis, enteritis and other inflammatory bowl disease.

16. C- Topical Agents
Sodium sulfacetamide ophthalmic solution or ointment is used for
Bacterial conjunctivitis
Trachoma
Silver sulfadiazine used for prevention of infection of burn wounds.

17. Nocardiosis:
Sulfisoxazole or sulfadiazine

18. Used in combination
Pneumocystis Carinii – sulfamethoxazole combined with trimethoprim (Co-trimoxazole)
Resistant Malaria (Sulfadoxine + Pyrimethamine – Fansidar)
Acute toxoplasmosis – (Sulfadiazine + Pyrimethamine)

19. ADVERSE EFFECTS
Hypersensitivity Reactions:-
1. Fever, Skin rashes, exfoliative dermatitis, photosensitivity, urticaria, N, V, D Angioedema & Steven – Johnson syndrome
Stomatitis, conjunctivitis, arthritis and hepatitis.
2.Hematopoietic Disturbances :- Hemolytic or Aplastic anemia, Granulocytopenia, Thrombocytopenia, Leukemoid reactions
Can provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency.

20. Urinary Tract Disturbances:- Sulfonamides may precipitate in urine, especially at neutral or acid pH producing crystalluria, Hematuria or even obstruction and nephritis
Less with sulfisoxazole.
Treatment
Sodium bicarbonate and adequate hydration.

21. CONTRAINDICATIONS
Premature babies, newborns & infants less than 2 months
Pregnant woman at term – Kernicterus
Displacement of bilirubin from plasma albumin.
Deposition of bilirubin in basal ganglia and sub thalamic nuclei of brain.

22. Drug interactions Oral anticoagulants Sulfonylurea
Hydantoin anticonvulsants
Potentiate the effect of these drugs
Inhibition of metabolism or displacement from albumin

23. TRIMETHOPRIM
Chemistry:
Trimethoxybenzyl Pyrimidine
Chemically Related to anti malarial drug pyrimethamine both are folate antagonists.

24. MOA X X PABA Sulfonamides Dihydrofolic Acid (Folate) Trimethoprim
Dihydropteroate Synthetase X
Sulfonamides
Dihydrofolic Acid (Folate)
Dihydrofolate Reductase X
Trimethoprim
Tetrahydrofolic Acid
Purines
DNA

25. Pharmacokinetics
Given orally fully absorbed from GIT.
Distribution:- Widely distributed, in body fluids and tissues, including CSF concentrates in acidic media of prostatic and vaginal fluid.
PPB: 65 – 70 %
Excretion : in urine within 24 hrs.

26. Resistance Reduced cell permeability.
Overproduction of dihydrofolate reductase.
Production of altered reductase with reduced drug binding.
Resistance is plasmid encoded.

27. Clinical Uses Acute UTI: 100 mg – B.d.
Bacterial Prostatitis (Fluroquinolones are preferred )

28. CO-TRIMOXAZOLE Combination of trimethoprim with sulfamethoxazole.
Sulfamethoxazole – 400 mg Ratio 1:5
Trimethoprim – 80 mg.
One double strength tablet trimethoprim mg
Sulfamethoxazole 800 mg

29. Advantages of Using Co-Trimoxazole
Bactericidal. (Individual drugs are bacteriostatic)
Wide antibacterial spectrum.
More efficacy.
Less dose of each drug.
Less incidence of toxicity.

30. PHARMACOKINETICS
Can be given orally or I/V

31. MOA X X PABA Sulfonamides Dihydrofolic Acid (Folate) Trimethoprim
Dihydropteroate Synthetase X
Sulfonamides
Dihydrofolic Acid (Folate)
Dihydrofolate Reductase X
Trimethoprim
Tetrahydrofolic Acid
Purines
DNA

32. Antibacterial spectrum
Gram +ve and gram –ve organisms (resistant to individual drugs)
Chlamydia diphtheriae and N meningitidis.
E. coli, Proteus mirabilis, Proteus marginii, Enterobacter spp, Salmonella, Shigella, Pseudomonas and Serratia are inhibited.
Klebsiella, Brucella, Pasteuralia, Yersinia and Nocardia asteroids.

33. Bacterial Resistance
Plasmid mediated that codes for an altered dihydrofolate reductase.

34. Pharmacokinetics
Pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely matched to achieve a constant ratio of 20: 1 in their concentrations in blood and tissues.
Readily enters CSF and sputum.
Excreted through kidneys.

35. CLINICAL USES Pneumocystis jiroveci Pneumonia in AIDS patient
1. Respiratory infections:
Pneumocystis jiroveci Pneumonia in AIDS patient
Hemophilis influenzae
Streptococcus pneumoniae
Moraxella catarrhalis
Klebsiella pneumoniae
I/V use is for moderate to severe pneumocystis pneumonia, gram-negative bacterial sepsis
Caused by multidrug-resistant species.

36. Acute otitis media in children
Acute maxillary sinusitis in adults.

37. 2. GIT Infections: Shigellosis Systemic Salmonella infection (Typhoid Fever) 3. UTI uncomplicated, complicated and recurrent. 4. Prostatitis 5. Acute Gonococcal Urethritis 6. Non tuberculous mycobacterial infections

38. Prophylaxis in Neutropenic patients
Low dose therapy
Emergence of resistant bacteria limit its use.
Useful in carriers of Salmonella typhi

39. Adverse effects Folate deficient cells Megaloblastic anemia Leukopenia
Thrombocytopenia
75% of untoward effects involve skin
Nausea, vomiting, drug fever, vasculitis, renal damage, CNS disturbances.

40. Pyrimethamine and sulfonamide
Pyrimethamine + sulfadiazine used for treatment of leishmaniasis and toxoplasmosis.
Pyrimethamine + sulfadoxine used for Falciparum malaria.

41. Adverse Effects Hematological
Trimethoprim – Megaloblastic Anemia, Leukopenia, Granulocytopenia
Prevented by simultaneous administrations of folinic acid 6 – 8 mg/D which does not enter bacteria.
Rashes, Fever, Vasculitis

42. GIT dist. – Nausea, vomiting, Glossitis & stomatitis.
HIV patients with pneumocystis pneumonia shows fever, rashes, leukopenia, diarrhea, elevation of hepatic aminotransferases, hyperkalemia, hypernatremia.

43. That’s all for today