1. ANTI-TUBERCULOSIS DRUGS

2. TUBERCULOSIS Difficult to Treat Grow slowly Cell wall impermeable Inside macrophages Develop resistance Caseation & fibrosis

3. SUBPOPULATIONS OF TB BACILLI Rapidly growing with high bacillary load as in the wall of a cavitary lesion where oxygen tension is high & pH is neutral Spurturs within caseous material where oxygen tension is low but pH is neutral Slowly growing intracellular (macrophages) & at inflamed sites where pH is low Dormant: Totally inactive

4. PRINCIPLES IN THE TREATMENT Multiple drugs to which organisms are susceptible Given for sufficient period Never add a single drug to a failing regimen AIM  to provide the most effective therapy in the shortest period of time

5. ANTI-TB DRUGS FIRST LINE DRUGS Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol SECOND LINE DRUGS Kanamycin Capreomycin Thiacetazone Ethionamide Cycloserine Para-aminosalicylic acid Ofloxacin Ciprofloxacin Amikacin Rifabutin LESS EFFECTIVE MORE TOXIC

6. RAPIDLY GROWING (NEUTRAL) SLOWLY GROWING EXTRACELLULAR (NEUTRAL) SLOWLY GROWING INTRACELLULAR (ACIDIC) ISONIAZID +++/-+ RIFAMPICIN ++++ PYRAZINAMIDE 00+++ STREPTOMYCIN ++++/-0 ETHAMBUTOL +/-0

7. INTERMITTENT THERAPY Drugs given 2-3x/week Turnover of bacilli = 24 hours Bacilli most susceptible at growth phase

8. ISONIAZID

9. Inhibits synthesis of mycolic acid of the mycobacterial wal Bactericidal to both extracellular & intracellular rapidly growing tubercle bacilli Oral absorption complete in fasting state Readily diffuses to all tissues including CSF

10. ADVERSE REACTIONS Nervous system – Peripheral neuropathy, psychosis, alteration in sensorium – Severely malnourished, alcohol intake, pregnancy Liver – Formation of acetyl free radicals – Asymptomatic elevation of ALT to severe hepatitis Allergic rash (+) ANA on long term use (20%) Hemolysis in G6PD deficiency PREGNANCY CATEGORY C

11. SURVEILLANCE Pre-treatment liver function Repeat if symptom of fatigue, anorexia, nausea, vomiting, weakness & at 2, 4, 6 months

12. RIFAMPICIN

13. Inhibits DNA dependent RNA polymerase Bactericidal to intracellular & extracellular, slow & rapidly growing bacilli Complete oral absorption in fasting state Widely distributed to all tissues including CSF when BBB is inflamed Excreted via the biliary tract with enterohepatic recirculation, also in tears, saliva, sweat & stools

14. ADVERSE REACTIONS Hepatotoxicity – Increased in alcoholics Hypersensitivity Nausea and vomiting Discoloration of body fluids; permanent discoloration of contact lenses PREGNANCY CATEGORY C SURVEILLANCE – Liver function: Pre-treatment & repeat if with symptoms suggestive of hepatitis

15. INTERACTIONS DRUG METABOLIZING ENZYME INDUCTION Increased requirement for oral anti- coagulants, corticosteroids Decreased effectiveness of oral contraceptives, steroids, oral hypoglycemics, theophylline, anticonvulsants, cyclosporine, ketoconazole

16. PYRAZINAMDE

17. PYRAZINAMIDE Inhibits fatty acid synthase, disruption of membrane potential & energy production Bactericidal to intracellular organisms only at slightly acidic pH Well absorbed from the GIT Widely distributed to all tissues including CSF Given for only 2 months

18. ADVERSE REACTIONS Hepatotoxicity Hyperuricemia Nausea Cutaneous hypersensitivity PREGNANCY CATEGORY C SURVEILLANCE – Liver function – Uric acid

19. STREPTOMYCIN

20. Aminoglycoside  Inhibits protein synthesis Bactericidal to actively multiplying extracellular bacilli in alkaline medium & in caseous lining of the walls of cavitations CURRENT USE: Suspected or proven with resistance Not absorbed from GIT Distributed to most tissues, crosses inflammed BBB Eliminated unchanged through the kidneys

21. ADVERSE REACTIONS Ototoxicity – Vestibular dysfunction: Tinnitus & high frequency hearing loss Nephrotoxicity Paresthesia, dizziness, nausea Peripheral neuropath Allergy PREGNANCY CATEGORY D SURVEILLANCE – Audiogram – Creatinine, BUN

22. ETHAMBUTOL

23. Inhibits arabinosyl transferase – Inhibition of formation of mycolyl-arabinogalactan- peptidoglycan complex  increased cell wall permeability Bacteriostatic at usual doses – Used to inhibit emergence of microbial resistance to other drugs Bactericidal at higher doses – Used in intermittent therapy & for drug resistant TB Good oral absorption Distributed to most tissues except CSF

24. ADVERSE REACTIONS Retrobulbar neuritis – Impairment of visual acuity & red & green color vision – Dose related and duration related – Avoid using in patients below 6 years old GIT symptoms Hyperuricemia Hypersensitivity PREGNANCY CATEGORY B

25. PROPERTIES OF ANTI-TB DRUGS

26. MAIN PROPERTIES Bactericidal activity – Kills actively rapidly growing bacilli Sterilizing activity – Kills bacilli that are slow & intermittently growing Ability to prevent or delay emergence of resistance – Bacteriostatic

27. RAPIDLY GROWING (NEUTRAL) SLOWLY GROWING EXTRACELLULAR (NEUTRAL) SLOWLY GROWING INTRACELLULAR (ACIDIC) ISONIAZID +++/-+ RIFAMPICIN ++++ PYRAZINAMIDE 00+++ STREPTOMYCIN ++++/-0 ETHAMBUTOL +/-0

28. PRINCIPLE OF CHEMOTHERAPY OF TUBERCULOSIS

29. STREPTOMYCIN ISONIAZID, RIFAMPICIN PYRAZINAMIDE RIFAMPICIN, ISONIAZID RAPIDLY GROWING EXTRACELLULAR SLOWLY GROWING, INTRACELLULAR & CASEAOUS LESIONS INADEQUATE TREATMENT ADEQUATE BACTERICIDAL ACTION ADEQUATE STERILIZING ACTION INADEQUATE TREATMENT; PERSISTENT TREATMENT FAILURE ELIMINATION OF BACILLI ELIMINATION OF PERSISTERS RELAPSE LASTING CURE OF TUBERCULOSIS

30. DOTS Sustained political commitment Access to quality assured TB sputum microscopy Standardized short-course chemotherapy under proper case management conditions, including direct observation of treatment Uninterrupted supply of quality-assured drugs Recording & reporting system enabling outcome assessment of each & every patient & assessment of the overall program performance

31. RECOMMENDED TREATMENT REGIMENS

32. PATIENTSINITIAL PHASE CONTINUATION PHASE INew smear positive New smear negative PTB with extensive parenchymal involvement Severe concomitant HIV disease or severe extrapulmonary forms 2 HRZE4 HR IIPreviously treated smear positive PTB Relapse Treatment after interruption Treatment failure 2HRZES 1 HRZE 5 HRE IIINew smear negative PTB Less severe forms of extrapulmonary 2 HRZE4 HR IVChronic & MDR-TBRefer