1. أ . م . د. وحدة بشير اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul Sulphonamides 6

2. Objectives At end of this lecture, the students will be able to:
1- State the definition of Sulphonamide Antibiotic
2- Enumerate the classes of sulphonamides.
3- List the antibacterial activities, clinical uses and side effects of most important clinically used sulphonamides (Cotrimoxazole) .
- At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

3. Sulphonamides
- Sulphonamides, amongst the first successful chemotherapeutic agents, but are seldom prescribed alone except in developing countries, where they are still employed because of their low cost and their efficacy in certain bacterial infections, such as trachoma and those of the urinary tract.
- However, when cotrimoxazole was introduced in the mid-1970s, there was a renewed interest in the sulfonamides.
- Sulfa drugs differ from each other not only in their chemical and physical properties but also in their pharmacokinetics.

4. Mechanism of action of Sulphonamides
- In many microorganisms, dihydrofolic acid is synthesized from p-aminobenzoic acid (PABA), by the enzyme dihydrofolic acid (DHF) synthase that converts PABA to DHF which is subsequently converted by DHF reductase to tetrahydric folic acid (THF), and then to purines and DNA.

5. Mechanism of action of Sulphonamides
- The sulphonamides are structurally similar to PABA, so they are successfully compete with it for DHF synthase, thus they inhibit the synthesis of bacterial DHF which is subsequently converted to tetrahydrofolic acid (THF), purines and DNA and thus ultimately impair bacterial DNA formation.
- Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF.

6. Notes
1- Trimethoprim relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme.
2- Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of Sulphonamides.
3- The sulfa drugs, including cotrimoxazole, are bacteriostatic

7. Antibacterial spectrum
- Sulfa drugs are active against selected enterobacteria in the urinary tract and nocardia.
- In addition, sulfadiazine, in combination with the dihydrofolate reductase inhibitor (pyrimethamine), is the preferred form of treatment for toxoplasmosis and chloroquine-resistant malaria.

8. Classification and uses of Sulphonamides
A- Systemic use
1- Sulfamethoxazole-trimethoprim combination form Cotrimoxazole
2- Sulfadiazine (t l/2 10 h), Sulfametopyrazine (t1/, 38 h) and Sulfadimidine (Sulfamethazine) (t l/2 approx. 6 h, dose dependent) are available in some countries for urinary tract infections, meningococcal meningitis and other indications, but are not drugs of first choice
(because the resistance rates are high).

9. B- Topical application
Silver sulfadiazine: is used for prophylaxis and treatment of infected burns, leg ulcers and pressure sores because of its wide antibacterial spectrum which includes pseudomonads.
C- Miscellaneous
Sulfasalazine is used in inflammatory bowel disease, the sulfapyridine component acts as a carrier to release the active 5-aminosalicylic acid in the colon.

10. Trimethoprim
- Trimethoprim, is a potent inhibitor of bacterial dihydrofolate reductase, exhibits an antibacterial spectrum similar to that of the sulfonamides.
- Trimethoprim (t 1/2 10 h) has emerged as a useful broad spectrum antimicrobial on its own. It is active against many Gram-positive and Gram-negative aerobic organisms excepting the enterococci and pseudomonas aeruginosa; the emergence of resistant organisms is becoming a problem.
- Trimethoprim is most often compounded with sulfamethoxazole, producing the combination called cotrimoxazole.

11. Consist of: Sulfamethoxazole-trimethoprim combination
Cotrimoxazole
Consist of: Sulfamethoxazole-trimethoprim combination
- Which shows greater antimicrobial activity than equivalent quantities of either drug used alone.
- The optimum synergistic in vitro effect against most susceptible bacteria is achieved with 5:1 ratio of sulfamethoxazole to trimethoprim, although concentrations achieved in the tissues vary considerably.
- The combination was selected because of the similarity in the half-lives of the two drugs

12. Mechanism of action of cotrimoxazole
The synergistic antimicrobial activity of cotrimoxazole results from its inhibition of two sequential steps in the synthesis of tetrahydrofolic acid: Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic acid precursors, and trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.

13. Antibacterial spectrum and uses of cotrimoxazole
- Cotrimoxazole has a broader spectrum of antibacterial action than the sulfa drugs.
1- It is effective in the treatment of chronic UTI.
2- The treatment of bacterial prostatitis (although fluoroquinolones are preferred) and vaginitis.
3- Respiratory tract infections due to:
a- hemophilis infuenzae.
b- Pneumocystis jiroveci pneumonia (opportunistic infection complicating AIDs)
c- Prevention and treatment of pneumonia due to Pneumocystis carinii, a life-threatening infection in immunosuppressed patients
4- GIT infections:
a- Treatment of Shigellosis and nontypoid salmonella.
b-Ampicillin- or chloramphenicol-resistant systemic salmonella infections.
c- Management of carriers of salmonella typhi.

14. Adverse effects of Sulfonamides
1- Malaise, diarrhea, mental depression and rarely cyanosis, which latter is due to methaemoglobinaemia. These may all be transient and are not necessarily indications for stopping the drug.
2-Crystalluria: Nephrotoxicity develops as a result of crystalluria.
- Adequate hydration and alkalinization of urine prevent the problem by reducing the concentration of drug and promoting its ionization.

15. 3-Hypersensitivity: Such as rashes, angioedema, and Stevens-Johnson syndrome, are fairly common. The latter occurs more frequently with the longer-acting agents.
4- Hemopoietic disturbances: Hemolytic anemia is encountered in patients with glucose 6-phosphate dehydrogenase deficiency.
- Trimethoprim can produce the effects of folic acid deficiency.6 These effects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having very poor diets.

16. 5- Kernicterus: This disorder may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. The free bilirubin serum level is increased and then can pass into the CNS, because the baby's blood-brain barrier is not fully developed.

17. Drug Interaction with Sulfonamides
Displacement from binding sites on serum albumin by Sulfonamides cause transient potentiation of the action of some drugs, include:
1- The hypoglycemic effect of tolbutamide.
2- The anticoagulant effect of warfarin.
3- Free methotrexate levels may also rise.

18. Contraindications of Sulphonamides
Due to the danger of kernicterus, sulfa drugs should be avoided in :
1- Newborns
2- Infants less than 2 months of age
3- In pregnant women at term.

19. The End

20. أ . م . د. وحدة بشير اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul-2014
Aminoglycosides 6

21. Objectives At end of this lecture, the students will be able to:
1- State the definition of Aminoglycosides Antibiotics
2- Distinguish the antibacterial activities, clinical uses and side effects of different aminoglycosides.
- At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

22. II- Antibiotics act by Inhibition of protein synthesis Aminoglycosides
-Include:
Gentamycin, Tobramycin, Amikacin, Netlmycin, Sisomycin, Streptomycin, Framycetin, Neomycin.

23. Aminoglycosides
- They are group of antibiotics sharing the same chemical, pharmacological, mechanism of action & toxicological properties, differing only in the antibacterial activity.
- Streptomycin was obtained from streptomyces as griseous in 1944, cultured from a heavily manured field & also from a chicken's throat.

24. Mechanism of action of Aminoglycosides
- The aminoglycosides act by inhibiting the synthesis of bacterial proteins. This is usually achieved by binding of the drug to 30 S subunit of bacterial ribosome in such a way that incorrect amino acids sequences are entered into peptide chains. The abnormal proteins which result are fatal to the microbe.

25. Antibacterial Activity of Aminoglycosides
- Aminoglycoside are bactericidal.
- They are effective only against aerobic gram negative bacilli and Staphylococci Activity against Streptococci and anaerobes is poor.
Note:
Aminoglycosides are poorly absorbed when given orally and must be used parentrally for systemic infections.

26. Clinical uses Aminoglycosides
1-Treatment of G- bacillary infection particularly septicemia, renal, pelvic & abdominal sepsis.
- Gentamycin remain the drug of choice but Tobramycin preferred for infections caused by pseudomonas aeroginosa.
- Amikacin is reserved for infection caused by gentamicin resistant microorganism.

27. Clinical uses Aminoglycosides
2- Bacterial endocarditis (enterococcal, streptococcal & staphylococcal infection of heart valve).
Note: Usually here given in combination
with Penicillin( and given with cephalosporin or Vancomycin in allergic patient to penicillin).
3- Other infections like brucellosis, TB, plaque, Tularemia.

28. Clinical uses Aminoglycosides
4- Treatment of billiary tract infection due to susceptible to G- microorganism.
5- Treatment of UTI as acute pyelonephritis.
6-Topical uses:
a- Neomycin & Framycetin are effective topically as eye ointment or drops & ear drops.
b- Gentamicin & framycetin as creams, ointments and solutions for the treatment of infected burns, wounds or skin lesions.

29. Clinical uses Aminoglycosides
7- Neomycin is used orally :
a- For bowel preparation before surgery to reduce GIT bacterial populations.
b- Sometime used to sterilize the bowel (may be in combination with framycetin), who are to receive intensive immunosuppressive therapy & in hepatic coma.

30. Side Effects of Aminoglycosides
1. Ototoxicity:
- Both vestibular and auditory damage may occur causing hearing loss, vertigo, tinnitus, headache, dizziness or nausea.
Note:
Deafness may be irreversible & has been known to affect fetuses in utero.
Aminoglycosides contraindicated in pregnancy.

31. Side Effects of Aminoglycosides
2. Nephrotoxicity:
- All aminoglycosides are nephrotoxic.
- Dose related changes, usually reversible.
- The effect ranging from mild renal impairment to sever acute tubular necrosis (may be irreversible)
- It is more likely to occur with:
large doses, high blood levels, long duration of therapy, in elderly patients, renal disease and in patients receiving furosemide diuretic.

32. Side Effects of Aminoglycosides
3. Neuromuscular Blockade:
- Aminoglycosides may impair neuromuscular transmission and aggravate myasthenia gravis or cause a transient myasthenia syndrome.
4. Allergic reaction:
- Contact dermatitis is a common reaction to topically-applied Neomycin.
5. Other reactions: Skin rashes, hemolytic anemia, paresthesia and peripheral neuropathy.

33. The End