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ANTITUBERCULOUS DRUG
Situation in Bangladesh
• Major public health problem in Bangladesh.
• The country ranks sixth among 22 highest burden TB
...
Drug of Neglected Diseases (DNDs)
• Last 25 years, NO anti- TB drug has been
developed
• No anti- TB drugs even in the pip...
• Orphan Disease:
Any disease that affects a small percentage of the
population. condition that affects less than 200,000 ...
Tuberculosis
• Tuberculosis is an infectious disease caused by
Mycobacterium tuberculosis
• Mycobacterium tuberculosis can...
• Mycobacteria are intrinsically resistant to most
Antibiotic, Because they grow slowly compared
with other bacteria, anti...
• Mycobacterial species are intracellular
pathogens, & organisms residing within
macrophages are inaccessible to drugs
tha...
• The response of mycobacterial infections to
chemotherapy is slow, and treatment must be
administered for months to years...
• First-line drugs –
Isoniazid (bactericidal)
Rifampicin (bactericidal)
Pyrazinamide (bactericidal)
Ethambutol (bacteriost...
Justification of combination therapy
• Different mechanism of action provide additive
antibacterial effect
• Compliance –
...
• Some obstacles that can be overcome by combination
therapy –
– Most antibiotics are more effective against rapidly
growi...
– The lipid rich mycobacterial cell wall is
impermeable to many agents
– A substantial proportion of mycobacterial
organis...
• Steps of TB management –
–Step 1 BCG Vaccination: 80% world children
vaccinated relatively effective in
preventing serio...
Treatment Regimens
• DOTS (Directly Observed Treatment, Short-course
chemotherapy)
• Health workers observe patient taking...
Treatment Regimens & Success rate
• 9 months regimen
– Initial phase 2 months
• Isoniazid Rifampicin Ethambutol
– Continua...
TB
Diagnostic
Category
TB patient TB Treatment
Initial phase
(daily)
Regimens
Continuation
phase(3 times
weekly)
I New sme...
TB
Diagnostic
Category
TB patient TB Treatment
Initial phase (daily)
Regimens
Continuation
phase(3 times
weekly)
II Previo...
TB
Diagnostic
Category
TB patient TB Treatment
Initial phase (daily)
Regimens
Continuation
phase (3 times
weekly)
III New ...
Drug Clinical setting Daily dose
Rifampicin CHILD 10-20 mg/kg
Adults weighing <50 kg & in the
elderly
450 mg
Adults weighi...
Isoniazid
• Antibacterial activity limited against
mycobacteria
• Inhibits growth of resting microbes, kills
multiplying
•...
• Mechanism of action:
– not very clear.
–INH is a prodrug that is Isoniazid is a prodrug that is
activated by mycobacteri...
Mechanism of action:
Isoniazid is a prodrug
↓
activated by mycobacterial catalase-
peroxidase(KatG)
↓
forms a covalent com...
• Pharmacokinetics:
–Rapidly & completely absorbed from GIT.
–Wide distribution including CSF
–Penetrates & accumulates in...
• Adverse effects:
– Commonest – allergic skin eruption
– Drug fever
– Hepatitis in elderly & patients with liver
disease ...
– Peripheral neuropathy particularly common in
malnourished patients due to deficiency of
pyridoxine
• Explanation – INH i...
Rifampicin
• A semisynthetic derivatives of rifampicin, an antibiotic
produced by streptomyces mediterranei.
• Most active...
• Two Rifampicin derivatives available
– Rifampicin Rifabutin
• Mechanism of action:
Rifampin binds to the subunit of bact...
• Human RNA polymerase does not bind rifampin
and is not inhibited by it.
• Rifampin is bactericidal for mycobacteria.
• I...
• Pharmacokinetics:
–Used orally, IV formulations available.
–Well absorbed from GIT
–Widely distributed throughout the wh...
• Adverse effects:
– Rash, Thrombocytopenia, Flu like syndrome, Dizziness,
Confusion, Hemolysis
– Red discoloration of uri...
Pyrazinamide
• Synthetic, orally effective, bactericidal, antitubercular agent
used in combination with INH & rifampicin
•...
• Can kill persisters, i.e., semidormant
mycobacteria within the cell lysosome as well as
in macrophages after phagocytosi...
• Adverse effects:
-hepatotoxicity (v.high dose -in 1–5% of
patients),
–Arthralgia
–Urate retention can also occur & may p...
Ethambutol
• Dextroisomer, has antitubercular effect
• Bacteriostatic & specific for most strains of M.
tuberculosis & M. ...
• Resistance emerges rapidly if used alone,
always given in combination with other
antituberculous drugs.
• well absorbed ...
• Adverse effects:
– Optic neuritis (retrobulbar neuritis):
dose related side effect, initially
red/green color blindness ...
Streptomycin
• First antibiotic effective in the treatment of
tuberculosis
• Penetrates into cells poorly & is active
main...
• Used when an injectable drug is needed or
desired, principally in individuals with
severe, possibly life-threatening for...
2nd line drug for tuberculosis
Recommended In case of
• Resistance to first-line agents;
• Failure of clinical response to...
• MDR –TB : is a form of TB caused by
bacteria that do not respond to at least
INH & refampicin, the @ most powerful
anti ...
AntiTuberculous Drugs
AntiTuberculous Drugs
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AntiTuberculous Drugs

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AntiTubercular Drugs

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AntiTuberculous Drugs

  1. 1. ANTITUBERCULOUS DRUG
  2. 2. Situation in Bangladesh • Major public health problem in Bangladesh. • The country ranks sixth among 22 highest burden TB countries in the world. • It is estimated that about 70,000 people die every year due to TB. • In 2009, 160,735 TB cases were notified to Nation Tuberculosis Control Program (NTP). • Only 30 % of expected new cases are detected by national tuberculosis control program (NTP) • Other receive treatment from private sectors • One person get sick in every 2 minutes • One person dies in every 10 minutes
  3. 3. Drug of Neglected Diseases (DNDs) • Last 25 years, NO anti- TB drug has been developed • No anti- TB drugs even in the pipe line • Whereas, a number of drugs for diseases like Baldness Obesity Erectile dysfunction Why???
  4. 4. • Orphan Disease: Any disease that affects a small percentage of the population. condition that affects less than 200,000 people in the United States e.g. ribose-5-phosphate isomerase deficiency • Orphan Receptor: an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan. • Orphan Drug: a pharmaceutical agent that has been developed specifically to treat a rare medical condition condition that affects less than 200,000 people in the United States,"[2] or about 1 in 1,500 people.
  5. 5. Tuberculosis • Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis • Mycobacterium tuberculosis can lead to serious infections of the lungs, genitourinary tract, skeleton, & meninges • The disease may have to be treated for six months to two years • Resistant organisms readily emerge, particularly in patients who have had prior therapy or who fail to adhere to the treatment protocol.
  6. 6. • Mycobacteria are intrinsically resistant to most Antibiotic, Because they grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective • Mycobacterial cells can also be dormant & thus completely resistant to many drugs or killed only very slowly • The lipid-rich mycobacterial cell wall is impermeable to many agents
  7. 7. • Mycobacterial species are intracellular pathogens, & organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly • Finally, mycobacteria are notorious for their ability to develop resistance • Combinations of two or more drugs are required to overcome these obstacles & to prevent emergence of resistance during the course of therapy
  8. 8. • The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used • Five first-line antimicrobial agents are currently recommended for antituberculosis therapy • Second-line medications are more toxic, or have not been studied as extensively. • The second-line medications are useful in patients who cannot tolerate the first-line drugs or who are infected with mycobacteria that are resistant to the first-line agents
  9. 9. • First-line drugs – Isoniazid (bactericidal) Rifampicin (bactericidal) Pyrazinamide (bactericidal) Ethambutol (bacteriostatic) Streptomycin (bactericidal) • Second-line drugs – Amikacin Capreomycin Cycloserine Kanamycin Thioacetazone Clarithromycin Paraamino salicylic acid (PAS) Ciprofloxacin Levofloxacin Rifabutin Clofazimine
  10. 10. Justification of combination therapy • Different mechanism of action provide additive antibacterial effect • Compliance – Early clinical improvement leads to discontinuation,duration of therapy reduced as a result of combination • Emergence of resistance can be delayed – – Intracellular, long metabolic inactivity tends to develop early resistance • Individual dose reduction – – Theoretically suppose to minimize the possibility of adverse effects, however spectrum of adverse effects has increased
  11. 11. • Some obstacles that can be overcome by combination therapy – – Most antibiotics are more effective against rapidly growing organism than against slowly growing ones. Because mycobacterium are very slowly growing organisms, they are relatively resistant to antibiotics. INH inhibit growth of resting microbe & kills multiplying – Mycobacterial cells can also be dormant & thus completely resistant to many drugs – or killed only very slowly by the few drugs that are active. INH passes freely into mammalian cells, effective against intracellular organism. Rifampicin, pyrazinamide can kill semidormant within cells
  12. 12. – The lipid rich mycobacterial cell wall is impermeable to many agents – A substantial proportion of mycobacterial organisms are intracellular, resting within macrophages, & inaccessible to drugs that penetrate poorly. INH can penetrate caseous TB lesion. – Mycobacteria are notorious for their ability to develop resistance to any single drug. Combination of drugs are required to overcome these obstacles & to prevent emergence of resistance during the course of therapy
  13. 13. • Steps of TB management – –Step 1 BCG Vaccination: 80% world children vaccinated relatively effective in preventing serious but non-infective childhood TB –Step 2 Chemoprophylaxis: Treating infected TB people before they get sick. – INH 5mg/kg by mouth daily for 1 year in – »Immuno-suppressed patient »Unvaccinated contact (tuberculin positive) »Adolescents with high degree of tuberculin sensitivity –Step 3 Different Treatment Regimens
  14. 14. Treatment Regimens • DOTS (Directly Observed Treatment, Short-course chemotherapy) • Health workers observe patient taking medicine • A national TB control programme to monitor progress • Unsupervised daily regimen (6 months regimen) – Initial phase 2 months • Pyrazinamide • Isoniazid • Rifampicin • Ethambutol (Likelihood of drug resistance or seriously ill) – Continuation phase 4 - 5 months • Isoniazid • rifampicin
  15. 15. Treatment Regimens & Success rate • 9 months regimen – Initial phase 2 months • Isoniazid Rifampicin Ethambutol – Continuation phase 7 months • Isoniazid Rifampicin • 12 month regimen: inexpensive & reasonably effective – Twice weekly: nearly 100% effective • Streptomycin 1 gm I.M. • INH 15 mg/kg plus pyridoxin 10 mg orally – Daily: very cheap regimen which is 80-95% effective • INH 300 mg & thiacetazone 150 mg – single doses by mouth • Comparative success rates in Bangladesh – Smear positive cases with DOTS 80% – Unsupervised daily regimen 57%
  16. 16. TB Diagnostic Category TB patient TB Treatment Initial phase (daily) Regimens Continuation phase(3 times weekly) I New smear positive; New smear negative PTB with extensive parenchymal involvement or severe forms of extra PTB (e.g. meningial, miliary, pericardial, peritonial, massive unilateral/bilateral pleural effusion, spinal, intestinal, genitourinary & multi organ TB) 2 (HRZE) 4 fixed-dose combination daily for 1st 2 months followed by 4 Fixed drug combinations R – 150 mg INH – 75 mg Pyraz -400 mg Etham-275 mg 4 (HR)3 2 fixed drug combination thrice weekly for another 4 months 2 FDC contains  Rifam 150mg INH – 75mg
  17. 17. TB Diagnostic Category TB patient TB Treatment Initial phase (daily) Regimens Continuation phase(3 times weekly) II Previously treated for > 1 month with sputum smear positive PTB with - Relapse/ -Treatment after interruption/ -Treatment failure 2 (HRZE)S/ 1 (HRZE) 4 FDC daily for 1st 3 month plus streptomycin injection 500 mg daily for 1st 2 months followed by  The dose of Streptomycin should not exceed 750 mg daily after the age of 50 years 5 (HR)3 E3 2 FDC + Ethambutol (400 mg) thrice weekly for next 5 months
  18. 18. TB Diagnostic Category TB patient TB Treatment Initial phase (daily) Regimens Continuation phase (3 times weekly) III New smear negative PTB (other than category I), Less severe form of extra PTB (e.g. lymph node, pleural effusion {unilateral}, bone {excluding spine}, peripheral joint, skin TB) 2 (HRZ) 3FDC daily for 1st 2 months followed by  4 (HR)3 2 FDC thrice weekly for another 4 months
  19. 19. Drug Clinical setting Daily dose Rifampicin CHILD 10-20 mg/kg Adults weighing <50 kg & in the elderly 450 mg Adults weighing >50 kg 600 mg Isoniazid CHILD 10 mg/kg Adults 200 – 300 mg Ethambutol CHILD & adults: Initial 8 weeks 25 mg/kg CHILD & adults: Subsequently 15 mg/kg Pyrazinamide CHILD & adults 20-35 mg/kg Streptomycin CHILD 30 mg/kg Adult 1 gm
  20. 20. Isoniazid • Antibacterial activity limited against mycobacteria • Inhibits growth of resting microbes, kills multiplying • Passes freely into mammalian cells, effective against intracellular organisms • For bacilli in the stationary phase, isoniazid is bacteriostatic, but for rapidly dividing organisms, it is bactericidal
  21. 21. • Mechanism of action: – not very clear. –INH is a prodrug that is Isoniazid is a prodrug that is activated by mycobacterial catalase- peroxidase(KatG) which forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, –which blocks mycolic acid synthesis, an important constituent of the cell wall of mycobacteria & kills the cell.
  22. 22. Mechanism of action: Isoniazid is a prodrug ↓ activated by mycobacterial catalase- peroxidase(KatG) ↓ forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase ↓ blocks mycolic acid synthesis(an important constituent of the cell wall of mycobacteria) & kills the cell.
  23. 23. • Pharmacokinetics: –Rapidly & completely absorbed from GIT. –Wide distribution including CSF –Penetrates & accumulates into caseous tuberculous lesion –Minimum tuberculostatic concentration is 25 – 30 ng/ml –Metabolized through N-acetylation • Slow acetylator half-life would be 3 hour (Drug causes toxicity, so peripheral neuropathy itself ) • Rapid acetylator ( by drug metabolite) half-life would be 1 hour (metabolite causes toxicity, so hepatotoxicity)
  24. 24. • Adverse effects: – Commonest – allergic skin eruption – Drug fever – Hepatitis in elderly & patients with liver disease & in rapid acetylators – Hemolytic anemia in G6PD deficiency – Arthritic symptoms – Decreased metabolism of anti-epileptic drugs like phenytoin, carbamazepine & ethosuximide. So their effects are increased
  25. 25. – Peripheral neuropathy particularly common in malnourished patients due to deficiency of pyridoxine • Explanation – INH is structurally analogue to pyridoxine & form a hydrazone ( a highly water soluble) with pyridoxal with no vitamin activity & the complex rapidly excreted in the urine • Measure to prevent – Pyridoxine 10 mg/day to prevent anticipated neuropathy
  26. 26. Rifampicin • A semisynthetic derivatives of rifampicin, an antibiotic produced by streptomyces mediterranei. • Most active antituberculosis agent • Effective against –Different mycobacteria - staphylococci –N. meningitidis - H. influenzae • It is a powerful hepatic enzyme inducer -  its own metabolism as well as other drugs like –phenytoin, OCP, glucocorticoids, –clarithromycin, ketoconazole, theophyllline, –clarithromycin
  27. 27. • Two Rifampicin derivatives available – Rifampicin Rifabutin • Mechanism of action: Rifampin binds to the subunit of bacterial DNA- dependent RNA polymerase and thereby inhibits RNA synthesis. • Resistance Mutation to the β subunit of bacterial RNA polymerase this result in binding of Refampicin to RNA polymerase .
  28. 28. • Human RNA polymerase does not bind rifampin and is not inhibited by it. • Rifampin is bactericidal for mycobacteria. • It readily penetrates most tissues and into phagocytic cells & Can kill both extracellular & intracellular microorganisms • It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities. • Attains effective concentration in CSF
  29. 29. • Pharmacokinetics: –Used orally, IV formulations available. –Well absorbed from GIT –Widely distributed throughout the whole body including CSF when meninges are inflammed –80 – 90% protein bound –Will cross placenta & distribute into the breast milk –t½ 3 hours –Metabolized in the liver. Undergoes enterohepatic cycling –Parent drug & metabolites are excreted via the bile & urine
  30. 30. • Adverse effects: – Rash, Thrombocytopenia, Flu like syndrome, Dizziness, Confusion, Hemolysis – Red discoloration of urine, tear & sputum is a useful indication that patient is taking the drug – Fatal hepatitis mainly being associated with prior liver disease • Indications: – TB – Leprosy – Pneumonia – Gonorrhoea – Chemoprophylaxis of meningococcal meningitis – Staphylococcal endocarditis(staphylococcal infections ) – Osteomylitis
  31. 31. Pyrazinamide • Synthetic, orally effective, bactericidal, antitubercular agent used in combination with INH & rifampicin • Prodrug, converted to pyrazinoic acid by pyrazinamindase of the m. tuberculosis • Inactive in neutral pH, tuberculostatic in acidic pH • It is bactericidal to actively dividing organisms, but the mechanism of its action is unknown
  32. 32. • Can kill persisters, i.e., semidormant mycobacteria within the cell lysosome as well as in macrophages after phagocytosis because pH of phagolysosome is low. • Distribute throughout the body, penetrate adequately to CSF, hence the drug is valuable in tuberculous meningitis • an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6-month) regimens as a "sterilizing" agent active against residual intracellular organisms that may cause relapse. • Safe to use in pregnancy
  33. 33. • Adverse effects: -hepatotoxicity (v.high dose -in 1–5% of patients), –Arthralgia –Urate retention can also occur & may precipitate a gouty attack –GI upset – anorexia, nausea, vomiting –Malaise –Fever –Urticaria, skin rash
  34. 34. Ethambutol • Dextroisomer, has antitubercular effect • Bacteriostatic & specific for most strains of M. tuberculosis & M. kansasaii • M/A: Inhibits mycobacterial arabinosyl transferases which involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. • Used as an alternative to streptomycin
  35. 35. • Resistance emerges rapidly if used alone, always given in combination with other antituberculous drugs. • well absorbed from the gut. • Taken up by the erythrocytes & slowly released. • About 20% of the drug is excreted in feces and 50% in urine in unchanged form. • Ethambutol crosses the blood-brain barrier only if the meninges are inflamed & Can penetrate CSF , use in TB meningitis.
  36. 36. • Adverse effects: – Optic neuritis (retrobulbar neuritis): dose related side effect, initially red/green color blindness followed by a  in visual acuity. Disappear following withdrawal of drug So,baseline opthalmic assesment is required. – Other adverse effects: Arthralgia, GI disturbance, Headache & mental disturbance – Peripheral neuritis: rare – Hypersensitivity: skin rash, fever, itching
  37. 37. Streptomycin • First antibiotic effective in the treatment of tuberculosis • Penetrates into cells poorly & is active mainly against extracellular tubercle bacilli • Crosses the BBB & achieves therapeutic concentrations with inflamed meninges • Nontuberculosis species of mycobacteria other than M. avium complex (MAC) & M. kansasaii are resistant to streptomycin
  38. 38. • Used when an injectable drug is needed or desired, principally in individuals with severe, possibly life-threatening forms of TB, e.g. meningitis & disseminated disease, & in treatment of infections resistant to other drugs • Adverse effect: dose related, & the risk is  in elderly –Ototoxicity & nephrotoxicity. Vertigo & hearing loss are most common & may be permanent.
  39. 39. 2nd line drug for tuberculosis Recommended In case of • Resistance to first-line agents; • Failure of clinical response to conventional therapy; • Serious treatment-limiting adverse drug reactions; and • When expert guidance is available to deal with the toxic effects.
  40. 40. • MDR –TB : is a form of TB caused by bacteria that do not respond to at least INH & refampicin, the @ most powerful anti TB drug • Extensively Drug Resistant( XDR-TB) is a form of MDR TB that respond to even fewer available medicine , including the most effective 2nd line anti TB drug.

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