Tuberculosis

complete information of tuberculosis including OLD RNTCP and new RNTCP with the novel drug that is marketed; classification of tuberculosis (MDR XDR TDR). special population and tuberculosis treatment clinical presentation and diagnosis

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2. TUBERCULOSIS PRESENTED BY: SHARIQUE RAZA M.PHARM 2 nd SEM JAMIA HAMDARD 2

3. CONTENTS Introduction Clinical presentation Diagnosis Classification Goals of antitubercular drug Keypoints in the treatment Pharmacotherapy RNTCP MDR,XDR &TDR Special population Novel drugs References 3

4. INTRODUCTION Tuberculosis is a communicable disease which is caused by bacteria (mycobacterium tuberculosis) that most often affect the lungs. Curable and preventable 4

5. Biology of tubercular infection M. tuberculosis is an aerobic organism. In unfavorable conditions it grows only intermittently or remains dormant for prolonged periods. Several subpopulations of bacilli, each with a distinctive metabolic state , could exist in an infected patient. 5

6. (a) Rapidly growing with high bacillary load : as in the wall of a cavitary lesion where oxygen tension is high and pH is neutral. These bacilli are highly susceptible to H and to a lesser extent to R, E and S. (b) Slow growing : located intracellularly (inside macrophages ) and at inflamed sites where pH is low. They are particularly vulnerable to Z, while H, R and E are less active, and S is inactive. 6

7. (c) Spurters : found mostly within caseous material where oxygen tension is low but pH is neutral: the bacilli grow intermittently with occasional spurts of active metabolism. R is most active on this subpopulation. (d) Dormant : some bacilli remain totally inactive for prolonged periods. No antitubercular drug is significantly active against them. However, there is continuous shifting of bacilli between these subpopulations 7

8. Classification Pulmonary TB Extra pulmonary i ) Lymph node TB ii)Pleural TB iii)TB of upper airways iv)Skeletal TB v)Genitourinary TB vi) Miliary TB vii)Pericardial TB viii)Gastrointestinal TB ix) Tuberculous Meningitis x)Less common forms 8

9. Clinical presentation Signs and Symptoms Patients typically present with weight loss, fatigue, a productive cough, fever, and night sweats. Frank hemoptysis. Physical Examination Dullness to chest percussion, rales, and increased vocal fremitus are observed frequently on auscultation . 9

10. Laboratory Tests Moderate elevations in the white blood cell (WBC) count with a lymphocyte predominance. Chest Radiograph Patchy or nodular infiltrates in the apical areas of the upper lobes or the superior segment of the lower lobes. Cavitation that may show air-fluid levels as the infection progresses . 10

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12. Diagnostic test Sputum smear microscopy , using the Ziehl-Neelsen staining technique. The Mantoux method of PPD (purified protein derivative) administration consists of the intracutaneous injection of PPD containing five tuberculin units. The test is read 48 to 72 hours after injection by measuring the diameter of the zone of in duration. 12

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14. Goals of antitubercular chemotherapy (a) Kill dividing bacilli : Drugs with early bactericidal action rapidly reduce bacillary load in the patient and achieve quick sputum negativity so that the patient is non-contagious to the community: transmission of TB is interrupted . This also affords quick symptom relief. (b) Kill persisting bacilli : To effect cure and prevent relapse. This depends on sterilizing capacity of the drug. (c) Prevent emergence of resistance: So that the bacilli remain susceptible to the drugs. 14

15. Key points in the treatment The therapy must contain two or more drugs to avoid development of resistance . Drugs must be taken regularly. Drug therapy must continue for a sufficient duration to achieve adequate therapeutic results. 15

16. PHARMACOTHERAPY FIRST LINE DRUGS High antitubercular efficacy as well as low toxicity. Used routinely. Isoniazid (H) Rifampin (R) Pyrazinamide (Z) Ethambutol (E) Streptomycin(S) SECOND LINE DRUGS Low antitubercular efficacy or higher toxicity or both Used as reserve drugs. Ethionamide (Eto) Prothionamide (Pto) Cycloserine (Cs) Terizidone (Trd) Para-amino salicylic acid (PAS) Rifabutin 16

17. Second line drugs continue…. FLUOROQUINOLONES Ofloxacin ( Ofx ) Levofloxacin ( Lvx ) Moxifloxacin ( Mfx ) Ciprofloxacin ( Cfx ) INJECTABLE DRUGS Kanamycin (Km) Amikacin (Am) Capreomycin (Cm) 17

18. ISONIAZID(H) It is primarily tuberculocidal . Fast multiplying organisms are rapidly killed, but quiescent ones are only inhibited. It acts on extracellular as well as on intracellular TB (bacilli present within macrophages), and is equally active in acidic or alkaline medium. It is one of the cheapest antitubercular drugs. Essential component of all antitubercular regimens, unless the patient is not able to tolerate it or bacilli are resistant. 18

19. MOA : inhibition of synthesis of mycolic acids which are unique fatty acid components of mycobacterial cell wall . PHARMACOKINETICS : completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta and meninges. It is extensively metabolized in liver; most important pathway being N- acetylation by NAT2. The acetylated metabolite is excreted in urine. 19

20. INTERACTION : Aluminium hydroxide inhibits absorption. retards phenytoin, carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4, and may raise their blood levels. rifampin is an enzyme inducer, its concurrent use counteracts the inhibitory effect of INH. PAS inhibits metabolism and prolong its t1/2. 20

21. Side effect : Lethargy, rashes, fever, acne & anthralgia ADVERSE EFFECT : Peripheral neuritis , numbness , mental disturbances, convulsion(rarely). 21

22. Rifampin semisynthetic derivative of rifamycin B obtained from Streptomyces mediterranei . Rifampin is bactericidal to M. tuberculosis. It is as efficacious as INH and better than all other drugs. Both extra- and intracellular organisms are affected. It has good sterilizing and resistance preventing actions. Mechanism of action : interrupts RNA synthesis by binding to β subunit of mycobacterial DNA-dependent RNA polymerase (encoded by rpoB gene and blocking its polymerizing function). 22

23. Pharmacokinetics: well absorbed orally,( bioavailability is ~ 70%), food decreases absorption; rifampin is to be taken in empty stomach. It is widely distributed in the body: penetrates intracellularly, enters tubercular cavities, caseous masses and placenta. crosses meninges, pumped out from CNS by P-glycoprotein. metabolized in liver to an active deacetylated metabolite which is excreted mainly in bile, some in urine also. undergo enterohepatic circulation . The t½ of rifampin is variable (2–5 hours). 23

24. INTERACTIONS: Rifampin is a microsomal enzyme inducer— increases several CYP450 isoenzymes, including CYP3A4, CYP2D6,CYP1A2 and CYP2C subfamily. It thus enhances its own metabolism as well as that of many drugs including:- warfarin, oral contraceptives, corticosteroids sulfonylureas, steroids, HIV protease inhibitors, Nonnucleoside reverse transcriptase inhibitors (NNRTIs), theophylline, metoprolol, fluconazole,ketoconazole, clarithromycin, phenytoin. 24

25. Pyrazinamide Weakly tuberculocidal and more active in acidic medium. highly effective during the first 2 months of therapy. Mechanism of action: converted inside the mycobacterial cell into an active metabolite pyrazinoic acid by an enzyme (pyrazinamidase) encoded by the pncA gene. This metabolite gets accumulated in acidic medium and probably inhibits mycolic acid synthesis . 25

26. Pharmacokinetics: absorbed orally, Widely distributed, has good penetration in CSF, because of which it is highly useful in meningeal TB extensively metabolized in liver and excreted in urine; plasma t½ is 6–10 hours. ADVERSE EFFECT: Hepatotoxicity , hyperuricaemia,abdominal stress, anthralgia, flushing, rashes, fever, loss of diabetes control(warned in diabetic patients). Contraindicated in pregnancy 26

27. Ethambutol selectively tuberculostatic . Added to the triple drug regimen of RHZ it has been found to hasten the rate of sputum conversion and to prevent development of resistance. MECHANISM OF ACTION : inhibit arabinosyl transferases (encoded by embAB genes) involved in arabinogalactan synthesis thereby interfering with mycolic acid incorporation in mycobacterial cell wall . 27

28. Pharmacokinetics: 3/4 of an oral dose of is absorbed. It is distributed widely, penetrates meninges incompletely and is temporarily stored in RBCs. Less than ½ is metabolized. It is excreted in urine by glomerular filtration and tubular secretion; plasma t ½ is ~4 hrs . Caution is required in its use in patients with renal disease. Adverse effect : Loss of visual acuity. Hyperuricemia . 28

29. Streptomycin tuberculocidal but less effective than INH or rifampin; acts only on extracellular bacilli (because of poor penetration into cells). It penetrates tubercular cavities, but does not cross to the CSF, and has poor action in acidic medium . lower margin of safety ( ototoxicity and nephrotoxicity , especially in the elderly and in those with impaired renal function) used only as an alternative to or in addition to other 1st line anti- TB drugs 29

30. Kanamycin (Km), Amikacin (Am) Tuberculocidal aminoglycoside antibiotics. Many S resistant and MDR strains of M.tuberculosis remain sensitive to them. One of these is mostly included in the regimen for MDR-TB during the intensive phase. produce less vestibular toxicity than hearing loss, but both are nephrotoxic. Patients should be instructed to report vertigo and tinnitus . Audiometry and monitoring of renal function is recommended . 30

31. Ethionamide (Eto) acts on both extra- and intracellular bacilli. MOA: converted by mycobacteria into an active intermediate which interferes with mycolic acid synthesis . PHARMACOKINETICS : completely absorbed orally, distributed all over and crosses into CSF. It is completely metabolized in liver and has a short t½ of 2–3 hours. Adverse effects are anorexia, nausea, vomiting, salivation, metallic taste, epigastric discomfort, sulfurous belching and hepatitis. It also causes aches peripheral neuritis, impotence, menstrual disturbances and goiter on prolonged use. 31

32. cycloserine tuberculostatic MOA : it inhibits bacterial cell well synthesis by inactivating the enzymes which racemize L- alanine and link two D- alanine residues. Oral absorption of Cs is good; it diffuses all over the body CSF concentration is equal to that in plasma. About 1/3 of a dose is metabolized; the rest is excreted unchanged in urine; plasma t½ is 9 hours. Adverse effects of Cs are primarily neurological; neuropsychiatric symptoms neurotoxicity and prevent convulsions. Cs is contraindicated in patients with a history of mental illness or seizures 32

33. Terizidone Same as cyloserine less neurotoxic ; reported incidence of adverse effects is lower. It is used as a substitute of Cs, especially in genitourinary TB , because it attains higher and longer lasting concentration in urine. 33

34. Para-amino salicylic acid Tuberculostatic MOA : inhibition of folate synthase . Pharmacokinetics : absorbed completely by the oral route and distributed all over except in CSF. It is excreted rapidly by glomerular filtration and tubular secretion; t½ is short, ~1 hour. Patient acceptability of PAS is poor because of frequent anorexia, nausea and epigastric pain. adverse effects are rashes, fever, malaise, hypokalaemia , goiter, liver dysfunction and rarely blood dyscrasias 34

35. Rifabutin It is related to rifampin in structure and mechanism of action. used as a substitute for R to minimise drug interactions due to strong enzyme inducing property of R. Rifabutin is a much weaker inducer of CYP enzymes than R. This is especially needed in HIV coinfected patients of TB who receive a protease inhibitor (PI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI) whose metabolism is markedly induced by R rendering them ineffective Oral bioavailability of rifabutin is low (~20%), but t½ is much longer (>30 hours ). 35

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38. RNTCP Revised National Tuberculosis Control Program  is the state-run tuberculosis (TB) control initiative of the Government of India. As per the National Strategic Plan 2012–17, the program has a vision of achieving a "TB free India", and aims to achieve Universal Access to TB control services. The program provides: various free of cost, quality tuberculosis diagnosis and treatment services across the country through the government health system. It seeks to employ the WHO recommended tuberculosis control strategy, DOTS (Directly Observed Treatment, Short Course), to the Indian scenario . 38

39. DOTS has five main components : Government commitment (including political will at all levels, and establishment of a centralized and prioritized system of TB monitoring, recording and training) Case detection by sputum smear microscopy Standardized treatment regimen directly of six to nine months observed by a healthcare worker or community health worker for at least the first two months A drug supply A standardized recording and reporting system that allows assessment of treatment results 39

40. Difference old NTP NTP : Less successful Inadequate funding Interrupted supply of drugs Low treatment compliance Over reliance on CXR for diagnosis RNTCP RNTCP : Moresuccessful Adequate funding Regular supply of quality assured drugs High treatment compliance due to the introduction of the DOTS regimen with directly monitered treatment. Reliance on sputum examination ,CXR,CBNAAT etc for diagnosis 40

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42. Mutiple drug resistant MDR-TB is defined as resistance to both H and R, and may be any number of other (1st line) drug(s). The general principles of treatment of MDR-TB are: The regimen should have at least 4 drugs certain to be effective. Often 5–6 drugs are included, since efficacy of some may be uncertain. Reliance about efficacy may be placed on survey of similar patients who have been treated, DST results (applicable to H, R, Km, Am, Cm, FQs), and the anti-TB drugs used previously in that individual . Avoid combining cross resistance drugs, e.g. two FQs, Km with Am or Eto with Pto , or Cs with terizidone 42

43. Include drugs from group I to group IV . Group I drugs (except H and R) can be included, add one injectable drug (group II), One FQ (group III) and one or two group IV drugs 43

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45. XDR These are MDR-TB cases that are also resistant to FQs as well as one of the injectable 2nd line drugs and may be any number of other drugs. The bacilli thus are resistant to at least 4 most effective cidal drugs, viz. H,R,FQ and one of Km/Am/Cm 45

46. TDR Totally drug-resistant tuberculosis (TDR-TB) is a generic term for tuberculosis strains that are resistant to a wider range of drugs than strains classified as  extensively drug-resistant tuberculosis. TDR-TB has been identified in three countries; India, Iran, and Italy . 46

47. SPECIAL POPULATION Treatment of breastfeeding women: All anti-TB drugs are compatible with breastfeeding; full course should be given to the mother, but the baby should be watched . The infant should receive BCG vaccination and 6 month isoniazid preventive treatment after ruling out active TB . 47

48. Pregnancy : Isoniazid or ethambutol are relatively safe for use in pregnant women. Rifampin is associated rarely with birth defects, including limb reduction and CNS lesions. Streptomycin use may lead to hearing loss in the newborn, including complete deafness Ethionamide may cause premature delivery and congenital deformities when used during pregnancy 48

49. Renal failure Isoniazid and rifampin do not require dose modification in renal failure, however the frequency of isoniazid dosing may be reduced. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly Renally cleared TB drugs include the aminoglycosides (Am, km, and s), capreomycin, ethambutol, cycloserine, and levofloxacin. Dosing intervals need to be extended for these drugs . The metabolites of isoniazid, pyrazinamide, and p -aminosalicylic acid are cleared primarily by the kidneys. Serum concentration monitoring must be performed for cycloserine to avoid dose-related toxicities in renal failure patients . 49

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51. AIDS PATIENT The metabolism of nucleoside reverse transcriptase inhibitors (NRTIs, zidovudine, etc.) is not induced by rifampin, and no dose adjustment is needed. An alternative regimen of 3 NRTIs (zidovudine + lamivudine + abacavir) has been advocated for patients who are to be treated by rifampin. If 2 NRTI + NNRTI is to be used, efavirenz should be selected as the NNRTI because its metabolism is induced to a lesser extent. MDR-TB in HIV-AIDS patients should be treated in the same way as that in non-HIV infected patient for a total of 18–24 months . 51

52. NOVEL DRUGS Nix-TB The Nix-TB trial is the first TB clinical trial to test a new drug combination which has the possibility of being a shorter, all oral, and affordable treatment for XDR-TB. This combination does not require injections and has far fewer pills. The Nix-TB drug combination is: Pretomanid ( inhibition of cell wall  mycolic acid  biosynthesis) bedaquiline (  blocks the proton pump for ATP synthase of mycobacteria ) and linezolid ( disrupts bacterial growth by inhibiting the initiation process of protein synthesis) This drug combination is predicted to be able to cure XDR-TB in six to nine months . 52

53. In February 2017 the results became available for the first 72 people to be treated in the study . Thirty one people have completed treatment and 6 months of post treatment follow up. Of these 31 people, 29 people cleared XDR-TB . This means that TB bacteria could no longer be cultured from their sputum. Twenty people stopped taking the drug after six months of follow up and only one relapsed. 53

54. AZD5847 AZD5847 is a potential new TB drug being developed by AstraZeneca. In December 2012 it was announced that the first patient had been enrolled in a Phase 2a trial of the drug in South Africa, to assess the effectiveness of the drug for patients with TB, including patients with  HIV and TB   coinfection .  The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the U.S. National Institutes of Health. 54

55. Nitroimidazoles derivatives of this class of drugs, OPC-67683 (now also known as delamanid ) and PA-824 are under development as potential TB drugs. 55

56. REFERENCE https://www.tbfacts.org/new-tb-drugs/ K.D.TRIPATHI essential of medical pharmacology 7 th edition. Joseph T. Dipiro Pharmacotherapy A pathological approach 8 th edition. 56

57. THANK YOU 57