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Anti Tubercular and anti leprotic agents.pdf

  1. By Imtiyaz Bagban M. Pharm. (Pharmacology) Assistant Professor Department of Pharmacology Krishna School of Pharmacy & Research (KSP) Drs. Kiran & Pallavi Patel Global University (KPGU) 1 B. Pharm. Semester VI Subject – Pharmacology Subject Code- BP602T UNIT 4 Antitubercular Agents
  2. Antitubercular Agents • Tuberculosis is a chronic granulomatous disease • In developing countries it is a major health problem • ≈ 30% of world population is infected with Myc. Tuberculosis infection • In India > 2 million people develop active disease every year & half million die.
  3. Tuberculosis • It is an infection difficult to treat • Typical growth characteristics • Peculiar cell wall structure (waxy appearance ) due to mycolic acid. • Resistance to infection emerges quickly. Mycobacterium tuberculosis
  4. Antitubercular Drugs Mycobacterium Infections Common infection sites • Lung (primary site) - Intestines • Brain - Lymph nodes • Bone • Liver • Kidney • Aerobic bacillus • Passed from infected: – Humans – Cows (bovine) and birds (avian) • Much less common
  5. Antitubercular Drugs Mycobacterium Infections • Tubercle bacilli are conveyed by droplets • Droplets are expelled by coughing or sneezing, then gain entry into the body by inhalation • Tubercle bacilli then spread to other body organs via blood and lymphatic systems • Tubercle bacilli may become dormant, or walled off by calcified or fibrous tissue
  6. Antitubercular Drugs Tuberculosis - Pathophysiology • M. tuberculosis – gram-positive, acid-fast bacillus • Spread from person to person via airborne droplets – Coughing, sneezing, speaking – disperse organism and can be inhaled – Not highly infectious – requires close, frequent, and prolonged exposure – Cannot be spread by hands, books, glasses, dishes, or other fomites
  7. Antitubercular Drugs Tuberculosis – Clinical Manifestations • Early stages – free of symptoms – Many cases are found incidentally • Systemic manifestations: – Fatigue, malaise, anorexia, weight loss, low-grade fevers, night sweats – Weight loss – occurs late – Characteristic cough – frequent & produces mucoid or mucopurulent sputum – Dull or tight chest pain • Some cases: acute high fever, chills, general flulike symptoms, pleuritic pain, productive cough • HIV Pt with TB: Fever, cough, weight loss – – Pneumocystic carinii pneumonia (PCP)
  8. Antitubercular Drugs Tuberculosis – Diagnostic Studies • Tuberculin Skin Testing -- + reaction 2-12 weeks after the initial infection – PPD – Purified protein derivative – used to detect delayed hypersensitivity response • Two-step testing – health care workers • 5mm > induration – Immunosuppressed patients • 10 mm> “at risk” populations & health care workers • 15 mm> Low risk people – Chest X-ray -- used in conjunction with skin testing • Multinodular lymph node involvement with cavitation in the upper lobes of the lungs • Calcification – within several years after infection – Bacteriologic Studies – • Sputum, gastric washings –early morning specimens for acid- fast bacillus -- three consecutive cultures on different days • CSF or pus from an abscess
  9. 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. Bacilli continuously shift from one to other subpopulation.
  10. Mycobacterial cell wall
  11. 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.
  12. Antitubercular Agents • Now there is emergence of multidrug resistant ( MDR ) TB . More than 0.4 million cases globally . History • First successful drug for treating TB was PAS (Para- aminosalicylic acid) developed by Lehman in 1943. • Dramatic success came when Waksman & Schutz discovered Streptomycin which has made remarkable progress. • Followed by Thiacetazone by Domagk in in 1946 • In 1952 Isoniazid came into being Pyrazinamide by Kushner & colleagues in 1952 & later on Rifampicin in 1957 by S. Margalith has totally changed the strategy in the chemotherapy. • Ethambutol came in 1961 by Lederle -laboratories • Fluoroquinolones, newer macrolides & congener of Rifampicin →Rifabutin are recent addition in antimycobacterial drugs
  13. Antitubercular Agents First line drugs: Ionized ( H) Rifampicin (R) Ethambutol (E) Pyrazinamide ( Z) Streptomycin ( S) now reserved drug in first line
  14. Antitubercular Agents Second line drugs: Thiacetazone Para aminosalicylic acid (PAS) Ethionamide Kanamycin Cycloserine Amikacin Capreomycin
  15. Antitubercular Agents Newer Second Line drugs: Ciprofloxacin Ofloxacin Levofloxacin Clarithromycin Azithromycin Rifabutin
  16. 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
  17. Antitubercular Agents Isoniazid (Isonicotinic acid hydrazide,H): Essential component of all anti TB regimen (except intolerance to H or resistance) -It is tuberculocidal , kills fast multiplying organism & inhibit slow acting organism -Acts both on intracellular ( present in macrophages ) & extracellular bacilli It is the cheapest AT Agent.
  18. Antitubercular Agents -Atypical mycobacteria are not inhibited by INH. Not active against any other micro-orgs. Mechanism of Action : Inhibit synthesis of mycolic acid ( unique fatty acid component of mycobacterial cell wall .)
  19. Antitubercular Agents • INH enters the bacilli by passive diffusion. It must be activated to become toxic to bacilli. It became toxic by Kat G (multifunctional Catalase - peroxidase , a bacterial enzyme ) • Which catalyzes the product from INH an Isonicotinoyl radical that subsequently inter-acts with mycobacterial NAD & NADP to produce dozen of adducts. • One of these a nicotinoyl NAD isomer which ↓ the activity of enoyl acyl carrier protein reductase (Inh A) & β- ketoacyl carrier protein synthase (Kas A) • Inhibition of these enzymes↓ the synthesis of mycolic acid an essential component of the mycobacterial cell wall & causes cell death.
  20. Antitubercular Agents (another adduct , a nicotinoyl –NADP isomer potentially mycobacterial dihydrofolate reductase → interfere with nucleic acid synthesis. These adducts also produce H2O2 , NO radical & other free radicals which are toxic to bacilli ) - If INH is given alone , inherent resistant bacilli proliferate selectively & after 2-3 months an apparently resistant infection emerges . (Mutation of the catalase –peroxidase gene in bacilli do not generate the active metabolite of INH ) - Combination therapy with INH has good resistance preventing action . - There is no cross resistance .
  21. Antitubercular Agents Pharmacokinetics : -Completely absorbed orally , penetrate all body tissues, tubercular cavities , placenta & meninges . - Metabolized in liver by acetylation & metabolites are excreted in urine . - Rate of acetylation shows genetic variation ( fast acetylators > 30% Indians - t½ -1 hr Slow acetylators >60% Indians -t ½- 3 hrs) (daily regimen is not affected but biweekly regimens are less effective in fast acetylators ) Dose – 4-6 mg/ kg for >50 kg – 300 mg daily - 600 mg bi-wkly
  22. Antitubercular Agents ADRs - Well tolerated drug 1.Peripheral neuritis & other neurological manifestations- parasthesia , numbness, mental disorientation & rarely convulsion ( due to interference with utilization of pyridoxine & ↑ excretion in urine ) Due to this Pyridoxine given prophylactically -10 mg/day which prevents neurotoxicities (INH neurotoxicity treated with Pyridoxine-100 mg/ day ) 2. Hepatitis – more common in older patients & alcohlics 3. Rashes , fever , acne & arthralgia .
  23. Antitubercular Agents D/I • interactions : Aluminium hydroxide it inhibits INH absorption. • INH inhibits phenytoin, carbamazepine, diazepam and warfarin metabolism: may raise their blood levels. • PAS inhibits INH metabolism and prolongs its t1/2.
  24. Antitubercular Agents Rifampin ( Rifampicin , R ): -Semisynthetic derivative of Rifamycin B from Streptomyces mediterranei -Bactericidal to M. Tuberculosis & others – S. aureus, Klebsiella, N. meningitidis, Pseudomonas, H. influenzae, Proteus, E. coli & Legionella. - Best action on slowly or intermittently dividing bacilli on extracellular as well as intracellular organisms -Also act on many atypical mycobacteria -Have good resistance preventing action
  25. Antitubercular Agents Mechanism: Inhibit DNA dependant RNA Synthesis (by ↓ bact RNA polymerase , selective because does not ↓ mammalian RNA polymerase ) - TB patient usually do not get primary Rifampicin resistance – If occurs is due to mutation in the repo -B gene (β subunit of RNA polymerase ). - No cross resistance
  26. Antitubercular Agents PKT – Well absorbed orally widely distributed in the body , penetrate cavities , caseous mass, placenta & meninges . -Metabolized in liver -Excreted mainly in bile & some in urine -t½- 2-5 hrs
  27. Antitubercular Agents ADR’s 1. Hepatitis – mainly in pts having preexisting liver disease & is dose related- Jaundice req. stoppage of drug 2. Respiratory syndrome –breathlessness, shock & collapse . 3. Purpura , hemolysis , shock , renal failure 4. Cutaneous syndrome – flushing , pruritis & rashes ( face & scalp ), redness & watering of eyes. 5. Flue syndrome – Nausea , vomiting, abdominal cramps 6. Urine & secretions may become red – which are harmless & Pt should be told about this effect.
  28. Antitubercular Agents D/I Rifampicin is microsomal enzyme inducer -↑ several CYP 450 isoezymes -↑ its own metabolism as well as of others e.g.-Oral contraceptive Digoxin Warfarin Theophylline Steroids Metoprolol Sulphonyl urea Fluconazole & Ketoconazole etc. (contraceptive failure can occur if given simultaneously in child bearing age women taking oral contraceptive)
  29. Antitubercular Agents Other uses – 1. Atypical myc. Inf. (M. kansasii, marinum , avium & intracellulare ) 2. Leprosy 3. Prophylaxis of meningococcal & H. infl. meningitis 4. Diphtheroids & legionella inf. 5. Along with Doxycycline –first line therapy in Brucellosis Dose- 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD
  30. Antitubercular Agents 3. Pyrazinamide ( Z) Chemically≡ INH -Weak tuberculocidal more active in acidic medium. -More lethal to intracellular bacilli & to those at sites showing an inflammatory response ( Therefore effective in first two months of therapy where inflammatory changes are present ) -Good sterilizing activity -It’s use enabled total duration of therapy to be shortened & risk of relapse to be reduced.
  31. Antitubercular Agents - Mechanism ≡ INH - ↓ fatty acid synthesis but by interacting with a different fatty acid synthesis encoding gene. - PZA is thought to enter M. tub. by passive diffusion and converted to pyrazinoic acid (its active metabolite) by bact. Pyrazinamidase enz. - This metabolite inhibits mycobact. Fatty acid synthase -I enz. and disrupts mycolic acid synthesis needed for cell wall synthesis. -Mutation in the gene (pnc A) that encodes pyrazinamidase enzyme is responsible for drug resistance ( minimized by using drug combination therapy) .
  32. Antitubercular Agents PKT : -Absorbed orally, widely distributed ,Good penetration in CSF. -Metabolized in liver & excreted in urine. -t½ -6-10 hrs
  33. Antitubercular Agents ADRs : - Hepatotoxic -dose related - Hyper uricaemia is inhibition of uric acid secretion in kidney - flushing , rashes , fever & anaemia - Loss of diabetic control Dose – 20-30 mg /kg daily , 1500 mg if > 50 kg
  34. Antitubercular Agents Ethambutol ( E) : -Tuberculostatic , clinically active as Streptomycin -Fast multiplying bact. are more sensitive -Also act against atypical mycobacteria -If added in triple regimen (RHZ) it is found to hasten the rate of sputum conversion & to prevent development of resist.
  35. Antitubercular Agents Mech. :Not well understood . Found to ↓arabinosyl transferase III involved in arabino galactone synthesis & also interfere with mycolic acid incorporation in mycobacterial cell wall. this is encoded by emb AB genes -Resistance develop slowly - No cross resistance
  36. Antitubercular Agents PKT: -3/4th of an oral dose of Ethm. is absorbed -Distributed widely but penetrates in meninges incompletely -½ metabolized , excreted in urine -caution is required in pts of renal disease -Pts acceptability is good & side efffects are low
  37. Antitubercular Agents ADRs: -Loss of visual acquity / color vision due to optic neuritis ,which is most impt. dose & duration dependent toxicity. (children can not report this complaint easily therefore not given below 6 yrs of age) -Early recognition –reversible Others- Nausea , rashes & fever -Neurological changes -Hyper uricaemia is due to interference with urate excretion Dose – 15-20 mg/kg , > 50kg -1000mg
  38. Antitubercular Agents Streptomycin (S): -It was 1st clinically useful antibiotic drug -It is protein synthesis inhibitor by combining with 30S ribosome -It is tuberculocidal , but less effective than INH / Rifampicin -Acts on extracellular bacilli only ( poor penetration in the cells )
  39. Antitubercular Agents -It penetrates tubercular cavities but does not cross BBB - Resistance when used alone (in average popul.1 in 10 to the power 8 bacilli are resistant to streptomycin –they multiply & cause relapse therefore stopped at the earliest .) - Atypical mycobact.s are ineffective - Popularity ↓ due to need of IM inj. & lower margin of safety ( because of ototox. & nephrotox.). - Dose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg
  40. MOA of 1st line drugs Mycolic Acid Arabinogalactan Peptidoglycan Cell membrane R I B O S O M e Protein Isoniazid - Pyrazinamide - Mitochondria (ATP) - Rifampin - Ethambutol - Streptomycin - Cytoplasm
  41. Antitubercular Agents Thiacetazone (TZN) : -First AT drug tested but weak -Discarded due to hepatotoxicity -In India revived in 1960s for oral use along with INH as a substitute to PAS - Tuberculostatic , does not add to the therapeutic effect of H,S, R, E ADRs - Hepatotoxic, Exfoliative dermatitis, Stevenson Johnson’s syndrome Can cause bone marrow depression Others- Nausea , anorexia , Abd. Discomfort, loose motions, Mild anemia, Pruritis Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined tablet with INH
  42. Mechanism of Resistance
  43. 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. Never use a single drug for chemotherapy in tuberculosis, a combination of two or more drugs must be used. Combination is synergistic
  44. Antitubercular Agents PAS – Paraaminosalicylic acid: -Related to sulfonamides chemically as well as in mech. of action. -Tuberculostatic , not add to therapeutic value , only delay resistance -Interfere with absorption of Rifampicin S/E - Acceptability is poor due to frequent anorexia , nausea & epigastric pain Other use- Goiter, Liver dysfunction & Blood dyscrasias Dose- 10- 12 gm ( 200 mg/ kg) / day Rarely used now
  45. Antitubercular Agents Ethionamide : -Tuberculostatic , having moderate efficacy -Acts both on extra as well as intracellular bacteria. Mechanism: Ethionamide is a prodrug which is activated by the enzyme ethA, a mono-oxygenase in Mycobacterium tuberculosis, and then binds NAD+ to form an adduct which inhibits InhA in the same way as isoniazid. The mechanism of action is thought to be through disruption of mycolic acid. -Resistance develop readily & some cross resistance to TZN -Absorbed orally ,distributed all over including CSF S/E- Anorexia, Nausea & vomiting, Rashes, Hepatitis, Peripheral/ Optic neuritis Dose- 1 gm / day, but more than 0.5 gm not tolerated. - seldom used now , only used in resistance cases .
  46. Antitubercular Agents Cycloserine (Cycs): - Obtained from S. orchidaceus & is a chemical analogue of D- alanine - Cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D- alanine ligase (Ddl). - The first enzyme which converts the L-alanine to the D-alanine form. - The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules. - If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together. - This effectively leads to inhibition of peptidoglycan synthesis -Tuberculostatic & ↓ other G +ve organisms ( E. coli , Chlamydia) -Resistance develop slowly , no cross resist. CNS toxicity is high , sleepiness , headache, tremor , psychosis & convulsions -Rarely used (only in resistance cases) Dose – 250 mg BD Kanamycin , Amikacin & Capreomycin: Used as reserved drug in severe cases not responding to usual therapy
  47. Antitubercular Agents Newer drugs : Ciprofloxacin Ofloxacin Levofloxacin ( all are used in TB & MAC ) Clarithromycin Azithromycin ( used in MAC ) Rifabutin - > in MAC < in TB
  48. Antitubercular Therapy Treatment of Tuberculosis : Remarkable change, conventional 1-1½yr Tt – is replaced by more effective & less toxic 6 month-8 month therapy a) Rapidly growing with higher bacillary load e.g. wall of the cavity region- highly suscep. to INH & lesser extent to R,E,S b) Slow growing – intracellular & at inflamed sites – vulnerable to Z while H,R,E are lesser active c) Spurturs - with in caseous material (where O2 tension is less) the bacilli grow intermittently. R- is most active in this sub population d) Dormant –bacilli remain totally inactive for prolonged periods- No ATT is effective
  49. Antitubercular Therapy Goals- 1. Killing of dividing bacilli- drugs with bactericidal activity rapidly reduce the bact. load in the Pt & achieve quick sputum clearance – Pt become non con-tageous to the community - Transmission is interrupted 2. Killing of persistent bacilli for effective cure & prevention of relapse 3. Prevent emergence of resistance (Drug combination are selected to maximize the above action together with consideration of cost & convenience ) H & R are most efficacious drugs ,their combination is synergistic
  50. Antitubercular Therapy Duration of therapy shortened from 12 to 9 months. Addition of Z for initial 2 months further reduces duration of treatment to 6 months DOTs –Directly observed treatment short course ,was recommended by the WHO in 1995 Short course chemotherapy- Regimen of 6-9 months treatment In 1997 WHO framed clear cut guidelines for different category of TB treatment . All regimen have initial intensive phase - 2-3 months to rapidly kill the TB bacilli & bring sputum conversion & afford symptomatic relief followed by continuation phase last 4-6 months for elementary remaining bacilli
  51. Antitubercular Therapy Categories: Category I –New ( untreated ) smear +ve pulmonary TB -New smear –ve pulmonaryTB with extensive parenchymal involvement -New cases of severe forms of extra- pulmonary TB e.g.- meningitis , miliary TB , pericarditis -Bilateral or extensive pleural effusion, intestinal or genitourinary TB (Revised National Tub. Control programme In India in 1997— DOTs –follow thrice wkly regimen to ↓ cost & it is more practical ) WHO : - 2 HRZE(S) (initial phase)-daily - 4 HR or 6 HE (continuation phase) daily total duration 6-8 months RNTCP : 2 H3R3Z3E3 + 4 H3R3 -total duration- 6month
  52. Antitubercular Therapy Category II -Smear +ve failure , relapse & interrupted Tt cases -Relapse- cured TB Patient again become sputum +ve -Tt after interruption –interrupted Tt x 2month →return to sputum + ve case WHO: Initial phase –daily 2 HRZES +1 HRZE Continuation phase –5 HRE - total 8 month RNTCP: Initial phase – 2 H3R3Z3E3S3 +1 H3R3Z3E3 Continuation phase -5 H3R3E3 –total 8 months
  53. Antitubercular Therapy Category III New cases of smear –ve pulmonary TB with limited parenchymal involvement or severe form of extra pulmonary TB . e.g.-Lymph node TB Unilateral pleural effusion Bone (excluding spine ) Peripheral joint & skin TB WHO : Initial phase -2HRZ (daily) Continuation phase - 4HR or 6HE (daily) Total duration-6-8 months RNTCP : Initial phase -2 H3R3Z3 ( daily ) Continuation phase -4 H3R3 ( daily ) Total duration- 6 months
  54. CATEGORY-WISE TREATMENT (WHO1997 & RNTCP1997) TB Category Initial Phase (daily /3xper week) Continuation Phase (daily/3xper week) Total Duration i. 2 HRZE(S)/ 2H3R3Z3E3 4 HR/ 4H3R3 or 6HE 6 8 ii. 2 HRZES+ 1HRZE / 2H3R3Z3E3S3+1H3R3Z3E 3 5 HRE or 5H3R3E3 8 8 iii. 2 HRZ/ 2H3R3Z3 4 HR/4 H3R3 or 6 HE 6 8
  55. Antitubercular Therapy DOTS PLUS: Refers to DOTS programme which includes component for multidrug resistance (MDR) tuberculosis , its diagnosis , management & treatment. (It began in 2000 by WHO & implemented in India in 2010 & thus category IV is created) .
  56. Antitubercular Therapy Cat IV – Chronic cases who have remained or become smear +ve after completing fully supervised Tt / close contact of most likely MDR cases MDR –TB –Resistant to both H & R & many other anti -TB drugs (Tt difficult because –one or more 2nd line drugs are to be given for 12-24 months & they are less efficacious , less convenient & more toxic & expensive ) Chronic – presence of association of AIDS /Diabetes / Leukemia /Silicosis -If sensitivity of drugs known then resistant drugs are excluded -For H resistance – RZE X 12 months - For H+ R resistance- ZE+ S / Kanamycin / Capreomycin/ + Ciprofloxacin or Ofloxacin ± Ethionamide could be used
  57. Antitubercular Therapy Extremely drug resistant (XDR) TB : Term applied to bacilli that are resistant to at least 4 most effective cidal drugs i.e. H ,R Ofloxacin , one of Kanamycin / Amikacin/ Capreomycin. Global survey –reveals 20% TB isolates are MDR out of which 2% are XDR .
  58. Antitubercular Therapy  TB in pregnant women : WHO – H,R,Z –safe (Recommended - – 2 HRZ + 6 HR regimen -8 month, -E can be added late, -S is C/I In India Z is avoided -(2 HRE + 7 HR total 9 month regimen )  Breast feeding mother: All ATT drugs are compatible ,baby should be watched ,the infant should receive BCG vaccination & INH prophylaxis  Indication of Glucocorticoids in TB: -In TB Pts, glucocorticoids if at all used are always used with AT drugs, they are considered in – - Miliary TB - Tuberculous Meningitis - Rapidly filling Pleural effusion & - Renal TB ( to reduce exudation & stricture formation) ( Its administration should be withdrawn gradually when the G.C. of Pts improved).
  59. RECENT DRUGS Three novel drugs currently under clinical development which are active against MDR-TB- 1. Linezolid 2. OPC-67683, a nitroimidazole 3. TMC207, a diarylquinoline ( Bedaquiline)
  60. Newer Antitubercular Drugs in Clinical Trials 1.LINEZOLID (Also known as 3rd line agent) • Linezolid is an oxazolidinone used primarily for the treatment of drug-resistant gram-positive infections. • Also active against M. tuberculosis • Mechanism of action is disruption of protein synthesis by binding to the 50S bacterial ribosome. • Linezolid has nearly 100% oral bioavailability, with good penetration into tissues and fluids, including CSF. • Adverse effects may include optic and peripheral neuropathy, pancytopenia, and lactic acidosis .
  61. Newer Antitubercular Drugs in Clinical Trials 2.TMC207 (R207910 ) by Andries etal in 2005 : • TMC207 is a new diarylquinoline with a novel mechanism of action: inhibition of the mycobacterial ATP synthetase proton pump. • TMC207 is bactericidal for drug-susceptible and MDR strains of M. tuberculosis. • Resistance has been reported and is due to point mutations in the gene coding for the ATP synthetase proton pump. • A phase 2 randomized controlled clinical trial demonstrated substantial improvement in rates of 2-month culture conversion, with improved clearance of mycobacterial cultures, for MDR-TB patients.
  62. Newer Antitubercular Drugs in Clinical Trials • This drug is metabolized by the hepatic cytochrome CYP3A4. • Rifampin lowers TMC207 levels by 50%, and protease inhibitors also interact significantly with this drug. • The dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly. • Adverse effects are reported to be minimal, with nausea and slight prolongation of the QTc interval.
  63. Newer Antitubercular Drugs in Clinical Trials 3. OPC-67683 AND PA 824 : • The prodrugs OPC-67683 and PA 824 are novel nitro- dihydro- imidazoxazole derivatives. • Antimycobacterial activity is due to inhibition of mycolic acid biosynthesis. • Early clinical trials of these compounds are ongoing.
  65. Changes in RNTCP Guidelines • Discontinuation of Cat III Regimen under RNTCP • The programme has now revised its categorization of patients from the earlier 3 categories (Cat I, Cat II and Cat III) to 2 categories (New and Previously treated cases)
  66. NEW (CAT I) New Sputum smear-positive New Sputum smear-negative New Extra-pulmonary New Others PREVIOUSLY TREATED (CAT II) Smear-positive relapse Smear-positive failure Smear-positive treatment after default Others
  67. TREATMENT Category Initial Phase Continuation Phase • New (Cat I) 2 H3R3Z3E3 4 H3R3 • Previously 2 H3R3Z3E3S3/ 5 H3R3E3 Treated 1 H3R3Z3E3 (Cat II)
  68. Anti- Leprotic agents • Also known as Hansen’s disease • It is a chronic granulomatous infection caused by Mycobacterium leprae • These bacteria grow very slowly and it may take up to 20 years to develop signs of the infection. • The disease can affect the nerves, skin, eyes, and lining of the nose (nasal mucosa). The bacteria attack the nerves, which can become swollen under the skin. • This can cause the affected areas to lose the ability to sense touch and pain, which can lead to injuries, like cuts and burns. • Usually, the affected skin changes color and either becomes: lighter or darker, often dry or flaky, with loss of feeling, or reddish due to inflammation of the skin.
  69. • If left untreated, the nerve damage can result in paralysis of hands and feet. • In very advanced cases, the person may have multiple injuries due to lack of sensation • Eventually the body may reabsorb the affected digits over time, resulting in the apparent loss of toes and fingers.
  70. • Corneal ulcers and blindness can also occur if facial nerves are affected. • Other signs of advanced Hansen’s disease may include loss of eyebrows and saddle-nose deformity resulting from damage to the nasal septum. • Disease is still considered as social stigma but it needs a change in the attitude of public to consider it just like any other disease . • Important is early diagnosis & Tt. Which makes it non infectious & prevents complcations.
  71. Treatment of Leprosy Classification: 1. Tuberculoid 2. Borderline 3. Lepromatous
  72. Treatment of Leprosy Tuberculoid: - Well defined skin lesion - Anesthetic patches - Organism may or may not be found in skin lesions. -Lepromine test is positpive. - Prolonged remission occurs Lepromatous: - Skin is thickened & glossy - Disease progresses – large nerve trunks get involved – anesthetic patches - Atrophy of skin & muscles & absorption of small bones e.g. phalanges of extremities, - Ulceration & spontaneous amputation occurs. - Lepromine test is –ve - Smear is +ve for organism .
  73. Anti- Leprotic agents Diagnosis of Leprosy: Diagnosed with any of the following- - Skin lesions ( hypopigmented patches ) - Impaired or loss of sensation - Acid fast bacilli in skin smears - Nerve thickening - Lepromin skin test
  74. Anti- Leprotic agents Anti- Leprotic drugs : Classification- -Sulfone- Dapsone (DDS) -Phenazine derivatives- Clofazimine -Antitubercular drugs- Rifampicin Ethionamide -Other Antibiotics - Ofloxacin , Minocycline & Clarithromycin
  75. Anti- Leprotic agents Sulfones - Derivative of 4-4’ diamino diphenyl sulfone (DDS) Dapsone: -Bacteriostatic -High risk of resistance if used alone Mechanism:  Similar to sulfonamide i.e. ↓ of dihydrofolate synthase enzyme.  Anti-inflammatory effect occurs via ↓ of migration of neutrophils to the inflammatory sites.
  76. Anti- Leprotic agents ADRs: -Nausea , vomiting , anorexia -Allergic reaction -Hemolysis in pts with G6PD deficiency -Methemoglobinaemia -Neurotoxicity & Psychosis Sulphone Syndrome: After 5/6 wks of Tt. in malnourished patients there may be characterized by fever, malaise , exfoliative dermatitis , lymph node enlargement, Jaundice etc.
  77. Anti- Leprotic agents Clofazimine : • It is a dye , weak bactericidal by ↓ the function of DNA. • Also having anti- inflammatory activity so prevents Lepra reaction. -used for common skin ulcers & MAC S/E- Skin- Red discolouration of skin GI- Enteritis with intermittent loose stools, nausea, abdominal pain, anorexia and weight loss can occur, particularly when higher doses used to control lepra reaction.
  78. Anti- Leprotic agents Rifampicin : - Important antiTb drug also bactericidal to M. Leprae. - Rapidly make leprosy Pts noncontagious - However not satisfactory if used alone- some bacilli persist after prolonged Tt –can cause resistance . Ethionamide - Has significant antileprotic activity but is hepatotoxic . It can be used as an alternative to Clofazimine but other substitutes are preferred.
  79. Anti- Leprotic agents Other Antibiotics: -Fluoroquinolones : Ofloxacin , Pefloxacin, Gatifloxacin are highly active against M. leprae ( but not Ciprofloxacin ) -Minocycline: due to high lipophilicity, it is active against M. leprae. , antibacterial activity is less than Rifampicin but more than that of Clarithromycin . Clarithromycin : Only macrolide antibiotic having significant activity against M. leprae . It is being included in alternative MDT regimens.
  80. Treatment of Leprosy • Leprosy primarily affect skin , mucous membranes & nerves • Prevalent in poors ( low socioeconomic strata ) . • National Leprosy Control Programme launched in 1955 • It was changed to National Leprosy Eradication Programme ( NLEP) in 1982 • India achieved elimination of Leprosy as a public health problem . Incidence is less than 1 case/ 10,000 population
  81. Treatment of Leprosy -For treatment purpose –leprosy is classified as- Single lesion paucibacillary –single dose ROM- Rifampicin-600 mg + Ofloxacin - 400mg + Minocycline-100 mg Paucibacillary : ( small no. of organism)- It includes indeterminate & tuberculoid Tt- Rifampicin – 600 mg / month supervised Dapsone – 100 mg / day self administration X minimum for 6 months-repeat if relapse
  82. Treatment of Leprosy Multibacillary - It includes lepromatous, borderline cases with +ve skin smear test Tt- Rifampicin - 600 mg / month supervised Dapsone-100 mg / day self administration Clofazimine – 300 mg/ month supervised + 50 mg/ day self administration X 2 years- relapse – repeat
  83. Treatment of Leprosy
  84. Treatment of Leprosy MDT was introduced by the WHO in 1981 & was implemented under the NLEP ( National Leprosy Eradication Programme). It includes Dapsone , Rifampicin & Clofazimine . The WHO in 1994 recommended a fixed duration therapy( FDT) of 2 years for MBL & 6 months for PBL. WHO expert committee On Leprosy in 1995 recommended shortening of MDT in MBL to 12 months & this was implemented in our country since 1999 . The purpose of this is to render the Pts noncontiguous & therefore cut down transmission
  85. Treatment of Leprosy Alternative regimens : Incorporating newer antileprotic drugs , but these are used only in case of Rifampicin resistance or when MDT is not advisable e.g.- Clofazimine + any two of Ofloxacin / Minocycline/ Clarithromycin for 6 months followed by Clofazimine + any one of Ofloxacin / Minocycline x additional 18 months .
  86. Treatment of Leprosy Two types of reactional state may occur with therapy 1. Type I : Lepra reaction (reversal reaction) In borderline leprosy due to increased in host immunity- skin lesion & nerves become swollen & tender without systemic manifestation – Tt. – Prednisolone (Thalidomide not effective)
  87. Treatment of Leprosy Type II :Lepra reaction ( erythema nodosum leprosum) –observed in lepromatous leprosy – there is skin & nerve manifestation with fever & systemic involvement. Tt.- by analgesic /antipyretic for mild cases, in severe cases- Prednisolone or Thalidomide. -Chloroquine & cytotoxic drugs are also effective. -Clofazimine require 3-4 wks so not suitable for acute cases, but useful in chronic cases & prevention of this reaction . - No need to stop the anti- leprotic drugs .
  88. MCQs 1. A middle aged man with chronic renal failure is diagnosed to have sputum +ve Pulmonary tuberculosis. His creatinine clearance is 25 mg/ min. All of the following Drugs need modification in doses EXCEPT : a) Isoniazid b) Streptomycin c) Rifampicin d) Ethambutol ( Ans- c ,Ref : Katzung 11/e p826) 2. A 30 year old pregnant women develops Tuberculosis. Which of the following antitubercular drug should not be given ? a) Rifampicin b) INH c) Streptomycin d) Ethambutol ( Ans- b ,Ref : KDT 6/e p748)
  89. MCQs 3. A patient suffering from AIDS is on Zidovudine ,Lamivudine and Indinavir therapy. He develops Pulmonary tuberculosis for which treatment is started. Which of the Following should be avoided in him ? a) INH b) Ethambutol c) Pyrazinamide d) Rifampicin ( Ans- d ,Ref : KDT 6/e p741) 4. A patient of multidrug resistant Tuberculosis is on antitubercular drugs. After a few Months he develops an inability to distinguish between red & green color. Most likely drug causing these symptoms is : a) Rifampicin b) Ethambutol c) Cycloserine d) Ethionamide ( Ans -b ,Ref : KDT 6/e p742) 5. In multidrug resistant strains of M. tuberculosis which of the following drugs is likely to be effective, including those resistant to Streptomycin? a) Amikacin b) Gentamicin c) Spectinomycin d) Clarithromycin ( Ans- a ,Ref: Katzung 11/e p825)
  90. MCQs 6. In atypical mycobacterial infection which of the following drug is active? a) Ethionamide b) Streptomycin c) INH d) Clarithromycin ( Ans- d , Ref: KDT 6/e p750) 7. Which of the following antitubercular drug DOES NOT cross blood brain barrier? a) Isoniazid b) Pyrazinamide c) Rifampicin d) Streptomycin ( Ans- d , Ref: KDT 6/e p743 ) 8. Which of the following anti-tubercular drug is implicated in the causation of transient memory loss? a) Ethambutol b) Ethionamide c) Pyrazinamide d) Isoniazid ( Ans –d , Ref : Goodman & Gilman 10/e p1277 )
  91. MCQs 9. Most effective drug for extracellular mycobacteria is: a) Ethambutol b) Rifampicin c) Isoniazid d) Pyrazinamide ( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 ) 10. In severe liver disease which of the following combination of antitubercular drug can be used ? a) Isoniazid + Streptomycin b) Rifampicin + Isoniazid c) Rifampicin + Ethambutol d) Streptomycin + Ethambutol ( Ans -d , Ref: KDT 6/e p 742-743 ) 11. In Leprosy , the best bactericidal agent is : a) Rifampicin b) Clofazimine c) Dapsone d) Ethionamide ( Ans-a ,Ref : KDT 6/e p753)
  92. MCQs 12. What is the side effect of Dapsone apart from hemolytic anaemia ? a) Infective mononucleosis like syndrome b) Flu like syndrome c) Lichenoid eruptions d) G-6-PD deficiency ( Ans -a , Ref: KDT 6/e p752 ) 13. Dapsone is used in all EXCEPT : a) Dermatitis herpitiformis b) Leprosy c) Pneumocystis jiroveci pneumonia d) Tuberculosis ( Ans -d , Ref: KDT 6/e p752 ) 14. In Lepra reaction , the drug useful is : a) Penicillins b) Clofazimine c) Dapsone d) Rifampicin ( Ans -a , Ref: KDT 6/e p752 )
  93. MCQs 15. Treatment of Lepromatous leprosy is : a) Rifampicin + Dapsone b) Rifampicin + Clofazimine c) Rifampicin + Dapsone + Clofazimine d) Rifampicin + Ofloxacin + Minocycline ( Ans -c , Ref: KDT 6/e p755 )
  94. Bibliography 1.Goodman & Gilman’s ,The Pharmacological Basis of Therapeutics (12th Edition). 2. A complete Textbook of Medical Pharmacology by S. K. Srivastava ( Latest Edition ) 3.. Essentials of Medical Pharmacology by K. D. Tripathi (7th edition)