Tuberculosis

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1. TUBERCULOSIS

2. CONTENTS: INTRODUCTION EPIDEMIOLOGY CAUSES PATHOGENESIS DIAGNOSIS TREATMENT

3. Tuberculosis  or  TB   is a common and often deadly infectious disease caused by mycobacteria, usually  Mycobacterium tuberculosis   in humans. Tuberculosis usually attacks the lungs   but can also affect other parts of the body.  The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss.

4. The primary cause of TB,  Mycobacterium tuberculosis , is a small  aerobic  non-motile  bacillus. The  M. tuberculosis  complex includes four other TB-causing  mycobacteria:  M. bovis ,  M. africanum ,  M. canetti  and  M. microti .  M. africanum  is not widespread, but in parts of Africa it is a significant cause of tuberculosis. CAUSES:

5. It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.   The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing. EPIDEMIOLOGY:

6.  In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in  developing countries. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5-10% of the US population test positive.

7. Per 1,000,00 10 - 24 < 10 25 - 49 50 - 99 100 - 299 300 or more No estimate Highest estimated TB rates per capita were in Africa

8. Pulmonary tuberculosis is a disease of respiratory transmission, Patients with the active disease (bacilli) expel them into the air by: coughing, sneezing, shouting, or any other way that will expel bacilli into the air Transmission is dependent on closeness and time of contact Transmission:

9. Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen: lung renal cortex reticuloendothelial system

10. When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs.  Symptoms include  chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include  fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to  fatigue very easily. Signs and symptoms:

11. In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the  pleura in tuberculosis pleurisy, the central nervous system in  meningitis, the lymphatic system in  scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. S igns and symptoms:

12. Infection via inhalation of droplet nuclei. ↓ Transport of bacilli to terminal alveoli (especially lower segments of lungs) ↓ Ingestion of organisms by macrophages followed by multiplication within macrophages ↓ Transport of organisms to regional lymph nodes by infected macrophages with continue multiplication and minimal inflammatory response Pathophysiology

13. ↓ Extension of organisms( within 4-6 weeks after inhalation) into the bloodstream from the regional nodes ↓ Cell mediated immunity / hypersensitivity reaction ↓ Development of clinical infection

14. D iagnosis by X-ray: Chest x-rays : Multi nodular infiltrate above or behind the clavicle with or without pleural effusion unilaterally or bilaterally.

15. D iagnosis sputum investigation: Cultures will reveal the presence of mycobacterium tuberculosis Patients stay infectious for as long as the bacilli are excreted in the sputum

16. D iagnosis by tuberculin test: Skin test . PPD (purified protein derivative) antigens are injected intradermally. A positive reaction is a helpful adjunct in diagnosis. Tuberculin test positivity indicated hypersentivity to bacterial protein

17. According to their clinical utility the drugs are: First line drugs : High antitubercular efficacy and low toxicity which are used routinely. Second line drugs: Either low antitubercular efficacy or high toxicity or both, used in special circumstances only. Classification of drugs:

18. First line drugs include: -ISONIAZIDE - PYRAZINAMIDE - ETHAMBUTOL -RIFAMPICIN -STREPTOMYCIN HIGH EFFICACY AND LOW TOXICITY

19. Second line drugs include: -THIACETAZONE -CAPREOMYCIN -P-AMINOSALICYLIC ACID -ETHIONAMIDE -CYCLOSERINE -KANAMYCIN -AMIKACIN LOW EFFICACY AND HIGH TOXICITY

20. NEWER SECOND LINE DRUGS: Flouroquinolones are active against M.tuberculosis. Ciproflaxacin, Oflaxacin, Newer macrolides and some rifampin congeners are the recent additions. Clarithromycin, Azithromycin, Rifabutin.

21. Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid bacteriostatic for resting bacilli, bactericidal for growing bacilli. ISONIAZIDE[H]:

22. Most active anti-tb drug. Dose:5mg/kg daily It inhibits cell wall sythesis or mycolic acid synthesis. Important assets are -potency -infrequent toxicity -low cost Useful for tb meningitis. Effective for both extra cellular & intracellular tb . If combined with other drug it has good resistance preventing action. ISONIAZIDE[H]:

23. ISONIAZID Kat G( catalase peroxidase in mycobacteria) Active INH AcpM & Kas AcpM- Acyl Carrier protein KasA ( ß ketoAcyl Carrier protein synthetase) Block Mycolic Acid Synthesis MOA of H:

24. Rash Peripheral Neuropathy Hepatitis Transient loss of Memory Seizure Pleural effusion Arthralgia Adverse Effects:

25. Semisynth. deri of Rifamycin B-from St.meditarranei. Acts both extra & intracellularly . Bactericidal efficacy ≈ INH &>any other 1 st line drug Analogue of RIFAMPIN is RIFABUTIN. obtained from Rifamycin S. Dose: 10mg/kg daily or 2-3 times weekly RIFAMPIN[R]:

26. D.N.A  RIFAMPIN  DNA dependent R.N.A.polymerase R.N.A  Protein Syn.  Cell multiplication Rifampin bind to β S.U of D.D.R.P  Drug –Enz Complex  Supression of chain initiation MOA OF RIFAMPIN:

27. Hepatitis, a major adverse effect. Respiratory syndrome: breathlessness. Purpura, haemolysis, shock and renal failure. Cutaneous syndrome : flushing, pruritis + rash. Flu like syndrome : fever, headache, bone pain. A dverse effects:

28. Synthetic analogue of Nicotinamide. Though weakly tuberculocidal  More active in acidic medium. Highly effective during 1 st 2months. More effective against Slow Growing. Active both intra & extracellularly. Dose : 20-25mg/kg daily PYRAZINAMIDE[z]:

29. Pyrazinamide Mycobacterial Pyrazinamidase Pyrazinoic Acid Inhibits Mycolic Acid Synthesis MOA OF PYRAZINAMIDE:

30. Adverse effects: Arthralgia Flushing Rashes Fever loss of diabetes control Hepatotoxicity

31. Rapid Growers are more susceptible. Prevent the emergence of Resistant bacilli. C/I ; Cr. Clearance <50ml/min Doses of Ethambutol : 15mg/kg/day ETHAMBUTOL[E]:

32. Mycobact. Arabinosyl Transferase  ETHAMBUTOL  Polymerisation reaction of Arabinoglycan  Essential component of Myco.Cellwall MOA OF E:

33. Loss of visual acuity Color blindness Field Defect Early recognition &stoppage of drug- visual toxicities is largely reversible Contra-indication ;In children <6yrs a) they are unable to report early. b) may not permit the assessment of red green color blindness discrimination  Renal uric acid excretion Hyperuricemia Joint Pain S ide effects:

34. First drug used for the treatment of TB. It is aminoglycoside antibiotic. It is tuberculocidal . It acts only on extracelluluar bacilli. Limitation of its use i )dose related toxicity ii)development of resistant org. iii)pt compliance is poor due to i . m STREPTOMYCIN

35. acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins. Streptomycin only binds to the 30s subunit. Dose: 15mg/kg 3 times weekly for first 2-3 months for severe disease H1 receptor blockers cause ototoxicity, with other aminoglycosides, diuretics and vancomycin MOA: INT:

36. SIDE EFFECTS: OTOTOXICITY-drugs get conc. In labrynthine fluid, both vestibular & cochlear damage NEPHROTOXICITY PARALYSIS Sterile abscess at the inj. site

37. Aminoglycosides: least effective and more toxic Capreomycin - Viomycin – Kanamycin Adverse effects: These drugs are: Nephrotoxic will cause Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects. S econd line drugs :

38. Can cause CNS disturbances Therapeutic States : Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs. It must be given in combination with other anti-tuberculosis drugs. Dose: 500 mg to 1g per day Mechanism of Action : An analog of D- alanine synthetase, will block bacterial cell wall synthesis. C ycloserine:

39. These are first anti tubercular drugs. It is a tuberculostatic drug. Low efficacy drug. Side effects: hepatitis, optic neuritis, mental disturbences impotence Dose: 150mg per day T hioacetazone & Ethionamide:

40. PAS is a tuberculostatic and one of least active drugs. It inhibits denovo folate synthesis. PAS is completely absorbed by oral route and distributed all over . Dose : 150 mg/kg/day Patient acceptability of PAS is poor. Adverse effects ; Rashes, fever, liver dysfunction P ara-amino salicylic acid:

41. Chemotherapy DOTS: To control tuberculosis requires: Effective, inexpensive, simple and standardised technology. The success of the DOTS strategy depends on: Government commitment to a national tuberculosis programme. Case  detection –finding by smear microscopy examination of TB susceptible in general health services. Regular uninterrupted supply of essential anti-TB drugs. Monitoring system for programme supervised and evaluation.

42. Short Course Chemotherapy: These are regimens of 6-9 month duration. All regimens have an initial intensive phase lasting 2-3 months to kill the TB bacilli and afford symptomatic relief. This is followed by continuation phase for 4-6 months so that relapse does not occur.

43. Type of patient Duration of treatment Regimen Category-1 1.New sputum positive 2.Seriously ill, sputum negative, Pulmonary 3.Seriously ill Intensive phase(2months) Continuation phase(4months) INH+RMP+ETB+PZA INH+RMP Category-2 Retreatment group 1.Relapse 2.Treatment failure Intensive phase(3months) Continuation phase(5months) INH+RMP+ETB+PZA INH+RMP+ETB Category-3 1.New smear negative pulmonary 2.extrapulmonary Intensive phase(2months) Continuation phase(4months) INH+RMP+PZA INH+RMP REGIMENS :

44. Multiple Drug Resistance(MDR): Resistance to both Isoniazid and Rifampin and number of other anti-TB drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks). Treatment is difficult as  second line drugs are less efficacious, less convenient, more expensive and toxic. Therapy depends on drugs used in earlier regimen, dosage and regularity with which they have been taken. In India>200,000patients have been treated under DOTS by early 2001 with cure rate of 75-80%. In other countries 80-93%cure rates have been obtained.

45. Chemotherapy Treatment of TB is categorised by: Site of disease (pulmonary or extra pulmonary), its severity: the bacillary load and acute threat to life are taken into consideration. Sputum smear positivity/negativity :positive cases are infectious. History of previous treatment: risk of drug resistance is more in irregularly treated patients.

46. WORLD TUBERCULOSIS DAY MARCH24 MARCH24

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