Chemotherapy of Tuberculosis

1. Chemotherapy of Tuberculosis

2. Tuberculosis • Chronic granulomatous disease. • Usually affects the lungs, up to one third of cases, other organs are involved.

3. Etiologic agent • Mycobacterium causes: • Tuberculosis • Mycobacterium avium complex disease • Leprosy

4. Mycobacterium tuberculosis complex: • Mycobacteriumtuberculosis : • Rod shaped, non- pore-forming, thin aerobic bacterium. • Important agent for human disease. • M. bovis • Important cause of tuberculosis for transmitted by unpasteurised milk. • M . africanum • West, central & east africa. • M .microti • Less virulent, rarely encountered organism.

5. M.tuberculosis transmitted from patient with infectious pulmonary Tb to other persons • By droplet nuclei, • Aerosolised by coughing, sneezing or speaking. • As many as 3000 infectious nuclei per cough.

6. Tiny droplets dry rapidly. • Smallest droplets (<10 um in diameter) • Suspended in the air for several hours , • May gain direct access to the terminal air passages when inhaled.

7. Risk factors for acquiring infection with M.Tuberculosis: • Probability of contact with the case of Tb. • Intimacy and duration of that contact. • Degree of infectiousness of the case. • Shared environment of the contact.

8. Risk factor for developing disease after being infected : • Individuals innate susceptibility to disease. • Level of function of cell mediated immunity.

9. Clinical manifestations • Pulmonary Tb • Primary • Secondary • Extra pulmonary Tb • Lymph node Tb • Pleural Tb • Tb of upper airways • Genitourinary Tb • Skeletal Tb • Tuberculous meningitis • Gastrointestinal Tb • Pericardial Tb • Miliary / disseminated Tb

10. Primary Tuberculosis • Results from initial infection with tubercle bacilli. • Children up to 4 yrs of age. • Middle, lower lung zone affected mainly. • Rapid progression to illness in HIV patients.

11. Pleural effusion: • due to penetration of bacilli into pleural space from subsequent subpleural area. • Lymphadenopathy: • due to spread of bacilli from lung parenchyma through lymphatic vessel. • Obstruction & subsequent segmental collapse: • as enlarged lymph node compress bronchi. • Obstructive emphysema: • due to partial obstruction. • Granulomatous lesions: • seen in severe cases as bacilli reach blood stream from pulmonary lesion/lymph nodes

12. Secondary Tuberculosis • Adult type. • Dormant bacilli, may persist for years before reactivating to produce Secondary Tuberculosis- often infectious. • Localised to the apical & posterior segments of the upper lobes , where high oxygen concentration favours mycobacterial growth.

13. Secondary Tb..... • Early symptoms: fever, night sweats, weight loss, malaise, weakness. • Development of Cough : non productive initially, production of purulent sputum.

14. Diagnosis of Tuberculosis

15. Treatment • Aim of treating Tuberculosis: • To interrupt tuberculosis transmission by rendering patients non-infectious. • To prevent morbidity & mortality by curing patients with tuberculosis disease.

16. Antitubercular drugs • First line drugs : • High efficacy & low toxicity. • Isoniazid 5mg / kg /d , max of 300 mg / d • Rifampin 10 mg/kg/d, max of 600 mg / d • Pyrazinamide 20-25 mg/kg/d, max of 2g / d • Ethambutol 15 -20 mg / kg / d • Streptomycin 15 mg / kg / d

17. Second line agentsEither low efficacy or high toxicity or both Slide 76

18. Isoniazid • Bacteriostatic for resting bacilli but bactericidal for rapidly dividing micro-organisms. • Minimal effective conc.: 0.025-0.05 ug/ml. • Peak plasma conc.: 1-2 hrs. • Good oral & parenteral absorption.

19. Metabolism via acetylation (acetylisoniazid) & via hydrolysis (isonicotinic acid).

20. N-acetyltransferase type 2 (NAT 2)

21. Mechanism of action….inh

23. Resistance • Mutation in catalase peroxidase • Decreases its activity • Prevent conversion of prodrug to active metabolite. • Mutation in inh A gene involved in mycolic acid biosynthesis. • Resulting in over expression of inh A.

24. Tuberculous cavity contains 109 micro-organism. • 1 in 106 bacilli genetically resistant to INH. • So, resistant mutants selected out in INH • monotherapy.

25. Adverse effects • INH induced hepatotoxicity. • Peripheral neuropathy. • Neurotoxicity. • Hematological reactions. • Hypersensitivity reactions.

26. INH induced hepatotoxicity. • Multilobular necrosis – by liver biopsy. • Risk factor : • Older age & excessive alcohol intake. • <20 years: Rare • 35-49 years & >50 years: elevated serum transaminase level. • > 5 times serum transaminase level: DISCONTINUE Drug.

27. Peripheral neuropathy: • Due to interference with utilization of pyridoxine and its increased excretion in urine. • Paresthesia of feet & hands. • Pyridoxine 10 mg/d for treatment.

28. Neurotoxicity: • Convulsion , in patients with seizure disorder. • Optic neuropathy. • Muscle twitching, stupor.

29. Hematological reaction: • Agranulocytosis, eosinophilia, thrombocytopenia. • Sideroblastic anemia (presence of ring sideroblasts in the bone marrow) • Reversible . • INH deprives ALAS2 (delta-aminolaevulinic acid synthase 2) of pyridoxal phosphate therefore inhibits haem synthesis. • Overcome by concomitant administration of pyridoxine(25 to 50 mg/d).

30. Hypersensitivity reaction: • Fever, rashes, hepatitis , SLE. INH overdose: • Tonic - clonic seizure, metabolic acidosis, coma in pregnant women. • Pyridoxine – specific antidote.

31. Management : • GI decontamination with gastric lavage, • Stabilization of vital signs with provision of patent airway and IV sodium bicarbonate, • Cardiovascular support with IV fluids and vasopressors. • IV pyridoxine – highly effective for INH intoxication and should be administered to all symptomatic patients.

32. Uses of INH • Latent Tb • Recent converters: who test positive within 2 years after a documented negative skin test. • Immunocompromised patients. • Prevention, in close contacts of active cases of pulmonary Tb.

33. INHᵡ Phenytoin • Effect : • Increased serum phenytoin level. • Slow acetylators – Phenytoin toxicity. • Mode : • INH – hepatic microsomal enzyme inhibitor. • Monitoring: • Need to monitor serum phenytoin level.

34. INH ᵡRifampin • Effect: • Hepatotoxicity. • Mode: • Altered INH metabolism by rifampin. • Monitoring: • If LFT alter, discontinue one or both agents.

35. Rifamycins • Rifampin • Rifabutin • Rifapentine

36. Mechanism of action: • Bactericidal at 3-12 ng/ml for both intracellular & extracellular microorganisms. • Kills organisms at poorly accessible sites like abscess, lung cavities.

37. Binds to β subunit of bacterial DNA dependent RNA polymerase. Suppression of initiation of chain formation but no chain elongation in RNA synthesis. Inhibit RNA synthesis in mammalian mitochondria, viral DNA dependent RNA Polymerase, reverse transcriptase at high concentration.

38. Mechanism of resistance • Mutation between codons 507 & 533 of polymerase rpo B gene “for β subunit of RNA polymerase. • Prevent binding of rifampin to RNA polymerase. • Alterations in the target of drug: • DNA dependent RNA polymerase.

39. Adverse effects • Hepatitis from rifampin rarely occurs in patients with normal hepatic function. • Chronic liver disease, alcoholism, and old age increase the risk of severe hepatitis when rifampin is given alone or concurrently with isoniazid. • < 5% of patients, serum level of aminotransferase, phosphatase, bilirubin increase slightly, but diminish spontaneously despite continuation of treatment.

40. Rifampin may potentiate toxic effect of INH, particularly in patients in whom INH is rapidly inactivated. • Rifampin induces microsomal enzyme. Facilitate conversion of monoacetylhydrazine, a metabolite of acetylated INH into an acylating agent that could cause hepatic necrosis.

41. Light chain proteinuria. • Imparts a harmless orange colour to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained)

42. GI disturbances – • (epigastric distress, nausea, vomiting, abdominal cramps, diarrhea) • occasionally required drug discontinuation. • Thrombocytopenia, transient leukopenia, and anaemia have occurred during therapy.

43. Rifampin × Anticoagulants • EFFECT : • Decreased anticoagulant effect. • MECHANISM: • Rifampin induces CYP2C9, CYP2C19, CYP2D6 • Increases elimination of other drug. • MONITORING: • Carefully monitor coagulation parameter. Adjust anticoagulant dose.

44. Ethambutol • Inhibit mycobacterial arabinosyl transferases, which is involved in polymerization reaction of arabinoglycan …….essential component of mycobacterial cell wall.

45. Adv. : • Retrobulbar neuritis causing loss of visual acuity and red-green colour blindness. (Serious). • Not recommended for children under 5 years of age because of concern about the ability to test their visual acuity.

46. Pyrazinamide PRODRUG Pyrazinoic acid pyrazinamidase (ACTIVE FORM) encoded by pnc A BACTERICIDAL Impaired mutation of pnc A RESISTANCE

47. Hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.

48. Streptomycin • Binds with S12 ribosomal protein. • Interfere with initiation of peptide formation. • Misreading of mRNA. • Breakup of polysomes into nonfunctional monosomes. • Irreversible inhibition of mycobacterial protein synthesis.

49. Ototoxic and nephrotoxic.(8th cranial nerve involves). • Vertigo and hearing loss -most common. may be permanent.

50. Ethionamide • Inhibits mycobacterial growth by inhibiting the activity of the enoyl-ACP reductase of fatty acid synthase II. • Thus inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.