anti-tubercular drugs prof. anuradha nischal. deadly infectious disease caused by mycobacterium...
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Anti-tubercular drugs
Prof. Anuradha Nischal
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• Deadly infectious disease caused by MYCOBACTERIUM TUBERCULOSIS
• Affects the lungs but can also affect other parts of the body.
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It is currently estimated that 1/2 of the world's population (3.5 billion) is infected with Mycobacterium tuberculosis.
Epidemiology
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• Pulmonary tuberculosis
• Droplets
• Patients with the active disease (bacilli) expel them into the air by:– coughing– sneezing
Transmission
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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
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Group 1
• First line oral ATDs
Group 2
• Injectible ATDs
Group 3
• Flouroquinolones
Group 4
• Second line oral ATDs
Group 5
• Drugs with unclear efficacy
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Group 1/First line drugs include:
ISONIAZID RIFAMPICIN PYRAZINAMIDE ETHAMBUTOL
most potent and best tolerated oral drugs HIGH EFFICACY AND LOW TOXICITY
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Group 2/Injectable ATDs
Streptomycin Kanamycin
AmikacinCapreomycin
potent, bactericidal, but injectable drugs
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Group 3/Flouroquinolones
Ofloxacin Levofloxacin
Moxifloxacin Ciprofloxacin(resistance) so removed
potent bactericidal well tolerated oral drugs. MDR
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Group 4/Second line oral drugs include: ETHIONAMIDE PROTHIONAMIDE CYCLOSERINE TERIZODONE p-AMINOSALICYLIC ACID
less effective, bacteriostatic, more toxic drugs for resistant tuberculosis
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Group 5/Drugs with unclear efficacy Thiacetazone
Clarithromycin Clofazimine Linezolid Amoxicillin/clavulanate Imipenem/cilastin
Drugs with uncertain efficacy, may be used for XDR
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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.
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MOA
• Inhibits mycolic acids synthesis (unique component MBCW)
• High selectivity for mycobacteria
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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
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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
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• 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
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Peripheral NeuropathyAnd 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
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• Q- Why Vitamin B6 is given with INH
Pyridoxine deficiency
Interference with activation of pyridoxine and its increased excretion in urine
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• Pyridoxine given prophylactically(10mg/day) prevents neurotoxicity
• INH neurotoxicity is treated by pyridoxine 100mg/day
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WHOM
Must: Diabetics, Chr. Alcoholics, malnourished, pregnant, lactating & HIV infected patients
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HepatitisCommon in older adults & alcoholicsDose related damage to hepatic cellsreversible
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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
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MOA
Rifampicin inhibits synthesis of R.N.A.
It binds to β 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).
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Other bacteria
Activity against other gram positive and gram negative bacteria
• Staph• N. meningitidis• H. influenzae• E.coli• Kleibseilla• Psuedomonas• Proteus• Legionella
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• M. leprae is highly sensitive• MAC & other mycobacteria are moderately susceptible.
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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
T1/2 varies from 2-5 hrs
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Adverse effects:HEPATITIS a major adverse effectUrine 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
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INTERACTIONSRifampicin 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
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Why should Rifampicin not given with OCP?
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Other uses
LeprosyProphylaxis of meningococcal & H. influenzae meningitis & carrier state
MRSABrucellosis.
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PYRAZINAMIDE
Weakly tuberculocidalMore active in acidic medium
More lethal to intracellular bacteria & bacteria at the site of inflammation Highly effective during 1st 2 months
By killing the residual intracellular bacteria it has good sterilizing activity
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• 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
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MOA
Pyrazinamide
Mycobacterial Pyrazinamidase
Pyrazinoic Acid (gets accumulated in
acidic medium)
Inhibits Mycolic Acid Synthesis
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+• Pyrazinoic acid also disrupts mycobacterial cell
membrane and its transport function
• Resistance develops rapidly if used alone & is due to mutation of gene pncA
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• Absorption : Well absorbed orally
• Distribution : good penetration to all body
tissue & CSF• Metabolism: extensively in liver
• Excreted in urine
T1/2 6-10hrs
Dose: 25-30mg/kg/dayAdverse effects:
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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, loss of diabetes control
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ETHAMBUTOL[E]
Only Tuberculostatic drug among 1st line drugs.
Added to RHZ hastens the rate of sputum conversion and prevents the development of resistance.
Primarily added for this reason.
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MOA E Inhibits Mycobact. Arabinosyl
Transferase III
Arabinogalactan synthesis
Essential component of Myco. Cell
wall; disrupts the assembly of mycobacterial cell wall.
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PK
• Absorption: Well absorbed from g.i.t.• Distribution : Widely distributed• T1/2 ~ 4hrs
• Excretion: Glomerular filtration & tubular secretion
Dose to be reduced in Renal failure
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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
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• Contra-indication; In children <6yrs and Creatinine clearance <50ml/min
• Hyperuricaemia
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FQs
• Ofloxacin• Levofloxacin• Ciprofloxacin• Moxifloxacin
New potent oral mycobactericidal drugs
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• Primary indication Drug resistant TBkey component of all regimens for MDR TB
• Alternative to first line
Substitution of Ethambutol with Mfx has been found to enhance rate of bacterial killing & cause faster sputum conversionPossibility of decreasing the duration of treatment to less than 6 months
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• Mfx is the most active FQ against M. TB• Lvx is more active than Ofx & Cfx
Dose:• Ofloxacin: 800mg OD• Levofloxacin 750 mg OD• Moxifloxacin 400mg OD
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Goal of AT CTx
• Kill dividing bacilli• Kill persisting bacilli• Prevent emergence of resistance.
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Goal of AT CTx
Kill dividing bacilli• Reduce bacillary load• Achieve quick sputum negativity• Patient non-contagious• Transmission interupted• Quick symptomatic reliefKill persisting bacilli• Effect cure & prevent relapse
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Goal of AT CTx
Prevent emergence of resistance.• So that bacteria remain susceptible to the drugs
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Short Course Chemotherapy
Who has introduced 6-8 months multidrug “short course” regimens under DOTS programme.
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•4 drugs
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Multidrug therapy
HRZE
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4 drugs/Multidrug therapy
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Why?????
• Use of single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 3/4th of patients.
• Combination:• H & R most potent bactericidalCombination synergisticDuration of therapy shortened from >12 months to 9 months
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• Z acts on intracellular bacteriaIt has very good sterilizing activityAddition 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
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• Cost• Convenience• Feasibility• Decreased resistance
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TREATMENT CATEGORIES
CATEGORY-I
New cases
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Category I
• New case • Sputum positive for Mycobacterium TB
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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
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Two phases
Intensive phase
Continuation phase
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Intensive phase
• 4-5 drugs• 2-3 months• Rapidly kill the bacilli
Bring about sputum conversionAfford symptomatic relief
Continuation phase
• 2-3 drugs• 4-5 months
Remaining (few) bacilli eliminatedSo that relapse does not occur
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Category Intensive phase Continuous phase
Duration(months)
Comment
I 2 HRZE daily 4 HR daily 6 Optimal
2 HRZE daily 4 HR thrice weekly
6 Acceptable if DOT ensured
2 HRZE thrice weekly
4 HR thrice weekly
6 Acceptable if DOT ensured
II 2 HRZES daily+1 HRZE daily
5 HRE daily 8 For patient with low/medium risk of MDR-TB.
Emperical (Standardized) MDR regimen
Emperical(Standardized)MDR regimen
18-24Till DST
For patient with high risk of MDR-TB.Failures, 2nd default, contact of MDR
Tt of TB Guidelines, 4th edition (2010), WHO , Geneva.
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Category two
• Thrice weekly option not available for retreatment categories
• Assess risk of MDR-TB (DST)
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Recommended dosesDrug Daily dose
mg/kg maximum
3 times per week dose
mg/kg maximum
Isoniazid 5(4-6) 300 mg 10(8-12) 900 mg
Rifamin 10(8-12) 600 mg 10(8-12) 600mg
Pyrazinamide 25(20-30) 35(30-40)
Ethambutol 15(15-20) 30(25-35)
Streptomycin 15(12-18) 15(12-18) 1000mg
Tt of TB Guidelines, 4th edition (2010), WHO , Geneva.
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Multiple Drug Resistance(MDR)
• Defined as Resistance to both Isoniazid and Rifampin (compulsorily) and number of other(1st line drugs)
• Rapid course With worse outcomes
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• 2.8% of all new cases• 12-17% of retreatment cases• Treatment is difficult as second line drugs are less efficacious, less convenient, more expensive and toxic for longer duration
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General principles
MDR Regimen• At least 4 drugs• Include drugs from group I to group IVGp I drugs (except H;R) 2+ one injectable; Gp II 1One FQ; Gp III 1One/two Gp IV drugs 2
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General principles
Gp I drugs
2; (except H;R)
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Standardized RNTCP regimen for MDR-TB
Intensive phase6 drugs; 6-9 months;
• Kanamycin• Ofloxacin• Ethionamide• Cycloserine• Pyrazinamide• Ethambutol
Continuous Phase4 drugs; 18 months
• Ofloxacin• Ethionamide• Cycloserine• Ethambutol
+ Pyridoxine 100 mg/day
RNTCP DOT plus guidelines;2010.
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Extensively Drug Resistant(XDR)• This term is applied to bacilli that are resistant to at
least four most effective cidal drugs, i.e. Cases resistant to INH Rifampicin Flouroquinolone and one of Kanamycin/Amikacin/Capreomycin
• Virtually untreatable• Mortality is very high, particularly among HIV positive patients.
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detected or diagnosed
• Standardized MDR regimen must be stopped immediately
• Expert panel may decide on instituting treatment with group v drugs
• Uncertain efficacy• Expensive
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Chemoprophylaxis
• INH: 300mg daily X 6 monthsChildren : 10 mg /Kg
• INH resistanceH(5 mg/kg)+R(10 mg/kg; max: 600 mg)X 3 months
• If INH cannot be used : R X 4 months
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Whom
• Contacts of open cases• Children with Mx positive & TB pt in the family• Neonate of TB mother• Pt of leukemia
–Diabetes– Silicosis–HIV positive–C. steroid therapy; who show +ve Montoux
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Pregnancy
• S contraindicated; ototoxicity
USA • Z not recommended
INDIA• Avoid Z• 2HRE+7HR
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• Treatment should not be withheld or delayed because of pregnancy
• All pregnant women being treated with INH should receive pyridoxine 10-25 mg/day
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Lactation
• All ATDs compatible with breast feeding• Full course should be given to mother
Infant: • BCG vaccination• 6 month INH prophylaxis after ruling out active TB.
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Thanks for your attention