Anti-tubercular drugs Prof. Anuradha Nischal. Deadly infectious disease caused by MYCOBACTERIUM...

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Transcript of Anti-tubercular drugs Prof. Anuradha Nischal. Deadly infectious disease caused by MYCOBACTERIUM...

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Anti-tubercular drugs Prof. Anuradha Nischal Slide 2 Deadly infectious disease caused by MYCOBACTERIUM TUBERCULOSIS Affects the lungs but can also affect other parts of the body. Slide 3 It is currently estimated that 1/2 of the world's population (3.5 billion) is infected with Mycobacterium tuberculosis. Epidemiology Slide 4 Pulmonary tuberculosis Droplets Patients with the active disease (bacilli) expel them into the air by: coughing sneezing Transmission Slide 5 Signs & symptoms A bad cough that lasts 3 weeks or longer Coughing up blood or sputum (phlegm from deep inside the lungs) Fever Weakness or fatigue Weight loss Anorexia mailaise Pain in the chest Slide 6 Group 1 Group 2 Group 3 Group 4 Group 5 First line oral ATDs Injectible ATDs Flouroquinolones Second line oral ATDs Drugs with unclear efficacy Slide 7 Group 1/First line drugs include: ISONIAZID RIFAMPICIN PYRAZINAMIDE ETHAMBUTOL most potent and best tolerated oral drugs HIGH EFFICACY AND LOW TOXICITY Slide 8 Group 2/Injectable ATDs Streptomycin Kanamycin Amikacin Capreomycin potent, bactericidal, but injectable drugs Slide 9 Group 3/Flouroquinolones Ofloxacin Levofloxacin Moxifloxacin Ciprofloxacin(resistance) so removed potent bactericidal well tolerated oral drugs. MDR Slide 10 Group 4/Second line oral drugs include: ETHIONAMIDE PROTHIONAMIDE CYCLOSERINE TERIZODONE p-AMINOSALICYLIC ACID less effective, bacteriostatic, more toxic drugs for resistant tuberculosis Slide 11 Group 5/Drugs with unclear efficacy Thiacetazone Clarithromycin Clofazimine Linezolid Amoxicillin/clavulanate Imipenem/cilastin Drugs with uncertain efficacy, may be used for XDR Slide 12 ISONIAZID[H] Cheapest ATD Mycobactericidal Bactericidal for rapidly growing bacilli Quiscent ones are only inhibited Extra and intracellular bacilli Equally active in acidic & alkaline medium. Slide 13 MOA Inhibits mycolic acids synthesis (unique component MBCW) High selectivity for mycobacteria Slide 14 MOA of INH: ISONIAZID Kat G( catalase peroxidase in mycobacteria) Reactive metabolite Inh A & Kas A Inh DHFR Inh DNA syn Inhibits the synthesis of Mycolic Acid Slide 15 Slide 16 Mechanism of Resistance High level resistance is due to mutation in catalase peroxidase (Kat G) gene Resistance may also develop due to mutation in Kas A & Inh A gene Efflux Of INH Loss of INH concentrating ability of bacteria Slide 17 Absorption: completely absorbed orally Distribution: penetrate all body tissue tubercular cavities, placenta & meninges Metabolism: in liver Excretion : in urine C/I known hypersensitivity acute hepatic disease Slide 18 Peripheral Neuropathy And neurological manifestations Paresthesias, numbness, mental disturbances most important dose dependent toxic effects. Pyridoxine deficiency Interference with activation of pyridoxine and its increased excretion in urine Slide 19 Q- Why Vitamin B6 is given with INH Pyridoxine deficiency Interference with activation of pyridoxine and its increased excretion in urine Slide 20 Pyridoxine given prophylactically (10mg/day) prevents neurotoxicity INH neurotoxicity is treated by pyridoxine 100mg/day Slide 21 WHOM Must: Diabetics, Chr. Alcoholics, malnourished, pregnant, lactating & HIV infected patients Slide 22 Hepatitis Common in older adults & alcoholics Dose related damage to hepatic cells reversible Slide 23 RIFAMPICIN[R] Semi synthetic derivative of Rifamycin B from St. meditarranei Bactericidal: Bactericidal efficacy INH Extra & intracellular bacteria Good sterilising property & resistance preventing action. All sub populations; best on spurters Slide 24 MOA RifampicinRifampicin inhibits synthesis of R.N.A. It binds to subunit of mycobacterial DNA dependent RNA polymerase & blocks its polymerising function Resistance develop due to mutation in rpo B gene( codes for RNA polymerase); X bind mammalian RNA polymerase (Basis for selectivity). Slide 25 Other bacteria Activity against other gram positive and gram negative bacteria Staph N. meningitidis H. influenzae E.coli Kleibseilla Psuedomonas Proteus Legionella Slide 26 M. leprae is highly sensitive MAC & other mycobacteria are moderately susceptible. Slide 27 Pk Absorption Well absorbed from g.i tract Food also interferes with abs; empty stomach Distribution widely distributed. Penetration intracellularly & enters tubercular cavities Caseous masses Placenta Metabolism Chiefly in liver to an active deacetylated metabolite. Which is excreted mainly in bile some in urine also. (30-70%). R and its metabolite undergoes enterohepatic circulation T 1/2 varies from 2-5 hrs Slide 28 Adverse effects: HEPATITIS a major adverse effect Urine and secretions become orange-red in colour Cutaneous syndrome Flu syndrome Abdominal syndrome SERIOUS BUT RARE Respiratory syndrome: breathlessness Purpura, haemolysis, shock and renal failure Slide 29 INTERACTIONS Rifampicin is a microsomal enzyme inducer It induces several CYP 450 iso enzymes Thus enhances its own metabolism as well as of other drugs including: Warfarin, OCPs, Corticosteroids, Anti-fungal drugs, Digitoxin, Protease inhibitors, NRTIs, etc. Increase dose; alternative method Slide 30 Why should Rifampicin not given with OCP? Slide 31 Other uses Leprosy Prophylaxis of meningococcal & H. influenzae meningitis & carrier state MRSA Brucellosis. Slide 32 PYRAZINAMIDE Weakly tuberculocidal More active in acidic medium More lethal to intracellular bacteria & bacteria at the site of inflammation Highly effective during 1 st 2 months By killing the residual intracellular bacteria it has good sterilizing activity Slide 33 Its inclusion has enabled duration of treatment to be shortened & reduced risk of relapse One third reduction in the duration of anti-TB therapy & a two third reduction in TB relapse This led to reduction in duration of therapy to 6 mths, producing the short course ctx Slide 34 MOA Pyrazinamide Mycobacterial Pyrazinamidase Pyrazinoic Acid (gets accumulated in acidic medium) Inhibits Mycolic Acid Synthesis Slide 35 + Pyrazinoic acid also disrupts mycobacterial cell membrane and its transport function Resistance develops rapidly if used alone & is due to mutation of gene pncA Slide 36 Absorption : Well absorbed orally Distribution : good penetration to all body tissue & CSF Metabolism : extensively in liver Excreted in urine T 1/2 6-10hrs Dose: 25-30mg/kg/day Adverse effects: Slide 37 Hepatotoxicity (dose dependent); occurs at 40mg/kg/day; hepatic disease in 15%. Regimens employed currently 15-30 mg/kg/day are much safer. Hyperuricemia; inhibits excretion of urates. In nearly all patients. May ppt acute episodes of gout. Arthralgia, nausea, vomiting, dysuria, malaise and fever, l oss of diabetes control Slide 38 ETHAMBUTOL[E] Only Tuberculostatic drug among 1 st line drugs. Added to RHZ hastens the rate of sputum conversion and prevents the development of resistance. Primarily added for this reason. Slide 39 MOA E Inhibits Mycobact. Arabinosyl Transferase III Arabinogalactan synthesis Essential component of Myco. Cell wall; disrupts the assembly of mycobacterial cell wall. Slide 40 PK Absorption: Well absorbed from g.i.t. Distribution : Widely distributed T 1/2 ~ 4hrs Excretion: Glomerular filtration & tubular secretion Dose to be reduced in Renal failure Slide 41 Side effects: Loss of visual acuity (reversible) loss of color vision Field Defect due to optic neuritis Dose & duration dependent toxicity. Pt should be instructed to stop the drug at first indication of visual impairment. Visual toxicity: reversible Slide 42 Contra-indication; In children Why????? Use of single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 3/4 th of patients. Combination: H & R most potent bactericidal Combination synergistic Duration of therapy shortened from >12 months to 9 months Slide 54 Z acts on intracellular bacteria It has very good sterilizing activity Addition of Pyrizinamide further reduces duration from 9 to 6 months E is bacteriostatic mainly serves to prevent resistance and may hasten sputum conversion Single daily dose AKT-4 Slide 55 Cost Convenience Feasibility Decreased resistance Slide 56 TREATMENT CATEGORIES CATEGORY-I New cases CATEGORY-II Previously treated patient. Slide 57 Category I New case Sputum positive for Mycobacterium TB Slide 58 Category II Smear positive TB patients Exposed to ATT in the past Did not complete the course Or took irregular medication Or relapsed after responding Failed to respond; failures Higher risk of harbouring DR bacilli Slide 59 Two phases Intensive phase Continuation phase Slide 60 Intensive phase 4-5 drugs 2-3 months Rapidly kill the bacilli Bring about sputum conversion Afford symptomatic relief Continuation phase 2-3 drugs 4-5 months Remaining (few) bacilli eliminated So that relapse does not occur Slide 61 CategoryIntensive phaseContinuous phase Duration (months) Comment I2 HRZE daily4 HR daily6Optimal 2 HRZE daily4 HR thrice weekly 6Acceptable if DOT ensured 2 HRZE thrice weekly 4 HR thrice weekly 6Acceptable if DOT ensured II2 HRZES daily + 1 HRZE daily 5 HRE daily8For patient with low/medium risk of MDR-TB. Emperical (Standardized) MDR regimen Emperical (Standardized) MDR regimen 18-24 Till DST For patient with high risk of MDR- TB. Failures, 2 nd default, contact of MDR Tt of TB Guidelines, 4 th edition (2010), WHO, Geneva. Slide 62 Category two Thrice weekly option not available for retreatment categories Assess risk of MDR-TB (DST) Slide 63 Recommended doses DrugDaily dose mg/kg maximum 3 times per week dose mg/kg maximum Isoniazid5(4-6) 300 mg10(8-12) 900 mg Rifamin10(8-12) 600 mg Pyrazinamide25(20-30)35(30-40) Ethambutol15(15-20)30(25-35) Streptomycin15(12-18)15(12-18) 1000mg Tt of TB Guidelines, 4 th edition (2010), WHO, Geneva. Slide 64 Multiple Drug Resistance(MDR) Defi