Drugs used in the treatment of tuberculosis

1. Drugs used in the treatment of tuberculosis Dr. Renu Agarwal

2. Lecture Objectives list the first line drugs currently used in the treatment of TB. describe the mechanism of action, pharmacokinetics and adverse effects of the following drugs: - Isoniazid. - Rifampin. - Ethambutol. - Pyrazinamide. - Streptomycin. 3. List the alternative second line drugs viz. ethionamide, capreomycin, cycloserine, aminosalicylic acid and briefly discuss their mechanisms of action and toxicities. 4. Discuss the rationale for combining these drugs used in treating pulmonary TB.

3. Tuberculosis It is an infection difficult to treat

4. M. tuberculosis: peculiar features Rapid growers: In the wall of cavitary lesion, extracellular. Slow growers: intracellular, within the macrophages at inflamed sites. Spurters: intermittent growth spurts. Dormant: Do not grow for long time, become active at times of low host resistance.

5. Mycobacterial cell wall

6. Chemotherapy in tuberculosis Goals of anti-tubercular chemotherapy Kill dividing bacilli: Patient is non-contagious : transmission of TB is interrupted. Kill persisting bacilli: To effect cure and prevent relapse. Prevent emergence of resistance: so that the bacilli remain susceptible to the drugs.

7. Drugs used in tuberculosis 1st line drugs high efficacy, low toxicity Isoniazid (INH) Rifampin Pyrazinamide Ethambutol Streptomycin 2nd line drugs Low efficacy, high toxicity or both Ethionamide Para aminosalicylic acid Cycloserine Amikacin/ Capreomycin Fluoroquinolones Rifabutin

8. MOA of 1st line drugs

9. Isoniazid (INH) Most active antitubercular drug. Bactericidal for rapid growers and bacteriostatic for slow growers. Effective against both intra- and extracellular bacilli.

10. INH � Adverse effects Peripheral neuropathy: INH promotes excretion of pyridoxine causing relative pyridoxine deficiency. Serious: Hepatotoxicity

11. Rifampin Bactericidal to M. tuberculosis and many gram + and � organisms. Effective against all subpopulations of mycobacteria (except dormant bacilli). Active against both extra- and intracellular organisms.

12. Rifampin: adverse effects The most common are rash, fever, nausea and vomiting Gives orange colour to urine and other body fluids. High dose: A flu-like syndrome. Rare but serious: hepatitis.

13. Pyrazinamide Weakly tuberculocidal. Active against intracellular bacilli.

14. Pyrazinamide: adverse effects Most common: Anorexia, nausea, vomiting, fever, arthralgia. Hyperuricemia in nearly all patients. Hepatitis

15. Ethambutol Tuberculostatic against rapid growers. Suppresses growth of most INH and streptomycin-resistant tubercle bacilli. Prevents resistance development.

16. Ethambutol: adverse effect Most common serious adverse effect is optic neuritis.

17. Streptomycin The first clinically available effective drug for the treatment of tuberculosis. Bactericidal. Effective only against extracellular bacilli.

18. Streptomycin: adverse effects Ototoxicity: vertigo & hearing loss. Nephrotoxicity

19. Relative activity of first line drugs INH: potent bactericidal Rifampin: potent bactericidal Pyrazinamide: Weak bactericidal, active against intracellular bacilli. Ethamutol: bacterisostatic, prevents resistance development. Streptomycin: bactericidal, active against extracellular rapid growers.

20. The Basis for Multi-Drug Therapy Prevent emergence of resistance

21. The Basis for Multi-Drug Therapy

22. Pharmacokinetics of 1st line drugs

23. ISONIAZID (INH): Pharmacokinetics

24. Anti TB drugs: effect on cytochrome enzymes INH is an enzyme inhibitor. Rifampin is a potent enzyme inducer

25. Compare and contrast 1st line drugs

26. 1st line drugs Treatment of tubercular infections. Always used in combination . Isoniazid is used alone for prophylaxis. Rifampin is also used in prophylaxis of meningococcal disease and H. influenzae meningitis. Streptomycin: is also used in gram negative infections.

27. Second line drugs in tuberculosis

28. 2nd line drugs Less efficacious More toxic Ethionamide, PAS, cycloserine: bacteriostatic. Amikacin/capreomycin/FQ are used in the treatment of MDR tuberculosis. Rifabutin is used in place of rifampin in HIV-infected patients.

29. Second line drugs in tuberculosis Failure of clinical response to 1st line therapy. Serious adverse drug reactions to 1st line drugs. Development of resistance to first-line agents.

30. Short course chemotherapy Highly efficacious, 6-9 months.

31. DOTS: directly observed therapy short course (WHO 1995) A health care worker watches the Tb patient swallow each dose of the prescribed medicine. This is done at a time and place convenient to patient. Direct observation ensures treatment of the entire course: with the right drugs in the right doses at the right interval It has tripled the treatment success in South-East Asia.

32. Multiple Drug Resistance(MDR) WHO: 450,000 new MDR-TB cases are estimated to occur every year. Resistance to both Isoniazid and Rifampin and any number of other anti-TB drugs. Treatment in such cases is extremely difficult. Amikacin/capreomycin/FQ

33. Chemoprophylaxis

34. Lecture Objectives list the first line drugs currently used in the treatment of TB. describe the mechanism of action, pharmacokinetics and adverse effects of the following drugs: - Isoniazid. - Rifampin. - Ethambutol. - Pyrazinamide. - Streptomycin. 3. List the alternative second line drugs viz. ethionamide, capreomycin, cycloserine, aminosalicylic acid and briefly discuss their mechanisms of action and toxicities. 4. Discuss the rationale for combining these drugs used in treating pulmonary TB.