This PPT covers drug therapy for tuberculosis. It includes classification of antitubercular drugs, chemotherapy for tuberculosis, strategies for addressing resistance and pharmacotherapy of antitubercular drugs

1. PREPARED BY: JEGAN NADAR
ANTIMALARIAL
DRUGS
ANTI TUBERCULAR DRUGS

2. Tuberculosis
 Tuberculosis is a chronic granulomatous disease and a major health
problem in developing countries.
 Tuberculosis (TB) is an infectious disease usually caused by
Mycobacterium tuberculosis (MTB) bacteria.
 Tuberculosis generally affects the lungs, but can also affect other parts of
the body.
 Most infections do not have symptoms, in which case it is known as latent
tuberculosis.
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3. Tuberculosis
 About 10% of latent infections progress to active disease which, if left
untreated, kills about half of those affected.
 The classic symptoms of active TB are a chronic cough with blood-
containing mucus, fever, night sweats, and weight loss
 It was historically called "consumption" due to the weight loss.
 Infection of other organs can cause a wide range of symptoms.
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4. Anti-TB Drugs
According to their clinical utility the anti-TB drugs can be divided into
● First line: These drugs have high antitubercular efficacy as well as low
toxicity; are used routinely.
● Second line: These drugs have either low antitubercular efficacy or
higher toxicity or both; and are used as reserve drugs.
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5. CLASSIFICATION
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6. CHEMOTHERAPY FOR TUBERCULOSIS
 M. tuberculosis is slow growing and requires treatment for months to
years.
 LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with
12 once-weekly doses of INH (900 mg) and rifapentine (900 mg).
 In contrast, active TB disease must be treated with several drugs
 Treatment for drug-susceptible TB lasts for at least 6 months, while
treatment of multidrug-resistant TB (MDR-TB) typically lasts for about 2
years.
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7. Strategies for addressing drug resistance
 Populations of M. tuberculosis contain small numbers of organisms that
are naturally resistant to a particular drug.
 Inadequate treatment, especially from monotherapy, these resistant TB can
emerge as the dominant population.
 Multidrug therapy is employed to suppress these resistant organisms.
 The first-line drugs isoniazid, rifampin, ethambutol, and pyrazinamide
are preferred because of their high efficacy and acceptable incidence of
toxicity.
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8. Strategies for addressing drug resistance
 Active disease always requires treatment with multidrug regimens, and
preferably three or more drugs
 Although clinical improvement can occur in the first several weeks of
treatment, therapy is continued much longer to eradicate persistent
organisms and to prevent relapse
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9. Isoniazid

10. Isoniazid
 Isoniazid is an excellent antitubercular drug, and an essential component
of all antitubercular regimens, unless the patient is not able to tolerate it or
bacilli are resistant.
 It is primarily tuberculocidal
 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
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11. Jegan Nadar

12.  About 1 in 106 tubercle bacilli is inherently resistant to clinically attained INH
concentrations.
 If INH is given alone, such bacilli proliferate selectively and after 2–3 months
an apparently resistant infection emerges.
 The most common mechanism which confers high level INH resistance is by
mutation of the catalase-peroxidase (KatG) gene so that the bacilli do not
generate the reactive metabolite of INH
 INH resistance may also involve mutation in the inhA or kasA genes
 Resistance based on efflux of INH from the bacterial cell is also possible.
 Other resistant TB bacilli lose the active INH concentrating process.
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13. Isoniazid
 INH is 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.
 The acetylated metabolite is excreted in urine.
 The rate of INH acetylation shows genetic variation.
Fast acetylators Slow acetylators
(30–40% of Indians) (60–70% of Indians)
t1⁄2 of INH 1 hr t1⁄2 of INH 3 hr
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14. Isoniazid- Interaction
 Aluminium hydroxide inhibits INH absorption.
 INH retards phenytoin, carbamazepine, diazepam, theophylline and
warfarin metabolism by inhibiting CYP2C19 and CYP3A4, and may raise
their blood levels
 PAS inhibits INH metabolism and prolongs its t1⁄2.
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15. Isoniazid-Adverse Effect
 INH is well tolerated by most patients.
 Peripheral neuritis and a variety of neurological manifestations
(paresthesias, numbness, mental disturbances, rarely convulsions) are the
most important dose-dependent toxic effects.
 Hepatitis, a major adverse effect of INH, is rare in children, but more
common in older people and in alcoholics
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16. Rifampin

17. Rifampin (Rifampicin, R)
 It is a semisynthetic derivative of rifamycin B obtained from
Streptomyces mediterranei.
 Rifampin is bactericidal to M. tuberculosis
 The bactericidal action covers all subpopulations of TB bacilli, but acts best
on slowly or intermittently dividing ones.
 M. leprae is highly sensitive, while MAC and some other mycobacteria, but
not M. fortuitum, are moderately susceptible
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19. Rifampin
 It is well absorbed orally, (bioavailability is ~ 70%), but 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.
 Though it crosses meninges, it is largely pumped out from CNS by P-
glycoprotein.
 It is metabolized in liver to an active deacetylated metabolite
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20. Rifampin
 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, NNRTIs, theophylline, metoprolol,
fluconazole, ketoconazole, clarithromycin, phenytoin, etc.
 Contraceptive failures have occurred
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21. Rifampin
 The incidence of adverse effects is similar to INH.
 Hepatitis, a major adverse effect, generally occurs in patients with
preexisting liver disease and is dose-related
 Minor reactions, usually not requiring drug withdrawal and more common
with intermittent regimens, are:
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22. Rifampin
 Cutaneous syndrome: flushing, pruritus + rash (especially on face and
scalp), redness and watering of eyes.
 Flu syndrome: with chills, fever, headache,malaise and bone pain.
 Abdominal syndrome: nausea, vomiting, abdominal cramps with or
without diarrhoea.
 Urine and secretions may become orange-red—but this is harmless.
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23. Pyrazinamide (Z)

24. Pyrazinamide (Z)
 Chemically similar to INH, pyrazinamide (Z) was developed parallel to it in
1952
 It is weakly tuberculocidal and more active in acidic medium.
 It is more lethal to intracellularly located bacilli and to those at sites
showing an inflammatory response
 By killing the residual intracellular bacilli it has good ‘sterilizing’ activity
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25. Jegan Nadar

26. Pyrazinamide (Z)
 Pyrazinamide is absorbed orally, widely distributed, has good penetration in
CSF
 Because of this it is highly useful in meningeal TB
 Extensively metabolized in liver and excreted in urine
 Plasma t½ is 6–10 hours
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27. Pyrazinamide (Z)
 Hepatotoxicity is the most important dose related adverse effect
 Daily dose is now limited to 25–30 mg/kg which produces only a low
incidence of hepatotoxicity.
 It is contraindicated in patients with liver disease.
 Hyperuricaemia is common and is due to inhibition of uric acid secretion in
kidney: gout can occur.
 Other adverse effects are abdominal distress, arthralgia, flushing, rashes
and fever Jegan Nadar

28. Ethambutol (E)

29. Ethambutol (E)
 Ethambutol is selectively tuberculostatic and is active against MAC as
well as some other mycobacteria, but not other types of bacteria.
 Fast multiplying bacilli are more susceptible.
 Added to the triple drug regimen of RHZ
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30. Jegan Nadar

31. Ethambutol (E)
 About 3/4 of an oral dose of Ethambutol is absorbed.
 It is distributed widely, but penetrates meninges incompletely and is
temporarily stored in RBCs.
 Less than ½ of Ethambutol is metabolized.
 It is excreted in urine by glomerular filtration and tubular secretion
 Plasma t½ is ~4 hrs.
 Caution is required in its use in patients with renal disease
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32. Ethambutol (E)
 Patient acceptability of Ethambutol is very good and side effects are few
 Loss of visual acuity/colour vision, field defects due to optic neuritis is
the most important dose and duration of therapy dependent toxicity.
 Patients should be instructed to stop the drug at the first indication of visual
impairment.
 Ethambutol produces few other symptoms: nausea, rashes, fever,
hyperuricemia and rarely peripheral neuritis.
 It is safe during pregnancy Jegan Nadar

33. Streptomycin (S)

34. Streptomycin (S)
 It is the oldest aminoglycoside antibiotic obtained from Streptomyces
griseus
 It was the first clinically useful antitubercular drug.
 It is tuberculocidal, but less effective than INH or rifampin
 Acts only on extracellular bacilli (because of poor penetration into cells).
 Thus, other drugs are needed to eradicate the disease.
 Resistance developed rapidly when streptomycin was used alone in
tuberculosis—most patients had a relapse Jegan Nadar

35. Jegan Nadar

36. Jegan Nadar

37. Streptomycin (S)
 Ototoxicity: This is the most important dose and duration of treatment
related adverse effect. The vestibular or the cochlear part is primarily
affected. Headache is usually first to appear, followed by nausea, vomiting,
dizziness, nystagmus, tinnitus, vertigo and ataxia
 Nephrotoxicity: It manifests as tubular damage resulting in loss of urinary
concentrating power, low g.f.r., nitrogen retention and albuminuria
 Hypersensitivity reactions are rare; rashes, eosinophilia, fever and
exfoliative dermatitis have been reported.
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38. Thank You