Tuberculosis is caused by Mycobacterium tuberculosis and spreads via droplet infection, mainly affecting the lungs. There are several types including primary, secondary, and miliary tuberculosis. Treatment involves a combination of antibiotics classified as first-line (isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin) or second-line drugs for resistant cases. The standard treatment regimen consists of a two month intensive phase with multiple antibiotics followed by a four month continuation phase with isoniazid and rifampin to prevent resistance. Directly observed therapy involves patients taking medications under supervision to improve adherence and cure rates.

1. ANTI TUBERCULOUS
AGENTS

2. Tuberculosis is a chronic granulomatous
inflammatory disease. The second leading
infectious cause of death in the world after
HIV. It spreads via droplet infection, main site
of infection is mid to upper zones of lungs.

3. PRIMARY TUBERCULOSIS
Occurs in previously unexposed people, 95% of
people have asymptomatic infection. 5% have
symptomatic infection with lobar consolidation,
hilar adenopathy and pleural effusion.
SECONDARY TUBERCULOSIS
Occurs in a previously exposed host, infection
occurs from re-activation of latent infection when
immune resistance is weakened.
Typically infection causes activation in apex of
upper lung lobes, with associated low grade fever,
night sweats and weight lose.

4. MILIARY TUBERCULOSIS
This disease is the result of acute diffuse
dissemination of tubercle bacilli via the blood
stream.
PATHOLOGY
Caseating Granulomas are characteristic of
tuberculosis, central necrotic tissue is surrounded
by lymphocytes and activated macrophages.
In primary tuberculosis there are lung and draining
lymph node granulomas known as the ghon
complex.

5. Caseous necrosis in TB

7. MYCOBACTERIA-TUBERCULOSIS
Mycobacteria are aerobic bacilli that grow
in chains and have a waxy cell wall composed of
mycolic acid, the cell wall retains certain dyes
after acid treatment.
Bactericidal drugs kill bacteria.
Bacteriostatic drug inhibits their growth but
does not kill them.

10. ANTI TUBERCULOUS AGENTS
Antituberculosis drugs are used mostly in the
treatment of tuberculosis, a granulamatous disease,
caused by Mycobacterium tubercuosis and also for
infections caused by various atypical mycobacteria.
CLASSIFICATION OF ATDs
Two types of classification of ATDs are followed;
a)First line and Second line drugs
b)Tuberculocidal and Tuberculostatic drugs

11. FIRST LINE DRUGS SECOND LINE DRUGS
Isoniazid (INH) Kanamycin (Kmc)
Rifampicin(RIF) Amikacin (Am)
Ethambutol(ETH) Cycloserine (Cys)
Pyrazinamine(PZA) Capreomycin (Cpr)
Streptomycin(S) Para amino salicylic acid(PAS)
Thiocetazone (Tzn) Ethionamide (Etm)
NEWER AGENTS
Quinolones
Clarithromycin
Azithromycin
Rifabutin
Rifapentine
Linezolid

12. TUBERCULOCIDAL
Isoniazid, Rifampicin, Pyrazinamide,
Streptomycin, Kanamycin, Amikacin, Capreomycin,
Quinolones.
TUBERCULOSTATIC
Ethambutol, Thiocetazone, Ethionamide, Para
amino salicylic acid, Cycloserine.

13. • Intensive phase
Standard short-course chemotherapy
for tuberculosis includes
isoniazid,rifampin, ethambutol, and
pyrazinamide for 2 months
• continuation phase;
• isoniazid and rifampin for 4 months

14. DOT therapy
• Patient adherence can be low when multidrug
regimens last for 6 months or longer
• directly observed therapy DOT is successful
strategy for achieving better treatment
• Patients take their medications while being
watched by a member of the health care team
• DOT has been shown to decrease drug
resistance and to improve cure rates

15. ISONIAZID (INH)
• primary drug in the treatment of tuberculosis
• ideal agent being bactericidal, relatively
nontoxic and easily administered.
• less effective against atypical Mycobacterial
species.
• penetrates into macrophages and is active
against both extracellular and intracellular
organisms.
• has structural resemblance with nicotinic acid
and pyridoxine.

16. MECHANISM OF ACTION
• The most plausible mechanism of action
of INH is the inhibition of synthesis of
mycolic acid, an important constituent of
mycobacterial cell wall
• Isoniazid is prodrug which is activated by
a mycobacterial catalase peroxidase to
exert its lethal effect

17. • The targeted enzymes are
1. enoyl acyl carrier protein reductase
(InhA)
2. beta ketoacyl-ACP synthase (KasA).
• activated drug covalently binds to
and inhibits these enzymes, which
are essential for the synthesis of
mycolic acid

18. Antibacterial spectrum
• Isoniazid is specific for treatment of M.
tuberculosis
• M. kansasii may be susceptible at higher drug
concentrations.
• Most NTM are resistant to INH
• particularly effective against rapidly growing
bacilli
• also active against intracellular organisms

19. PHARMACOKINETICS
• INH is completely absorbed orally
• penetrates all body tissues tubercular cavities,
placenta and meninges
• metabolized in liver by acetylation
• rate of INH acetylation shows genetic variation
• INH metabolites and small amount of
unchanged drug excreted mainly in urine
• Half life of INH in fast acetylators is 1 hour, and
in slow acetylators is 3 hours.

20. RESISTANCE
The most common mechanism of INH
resistance is by mutation of the catalase
peroxidase gene so that the bacilli do not
generate the active metabolite of INH.
It has no cross resistance with other
anti-tubercular agents.

21. ADVERSE EFFECTS
• INH has a low incidence(5%) of toxicity
• Peripheral neuritis (paresthesia due to
deficiency of pyridoxine
• mental disturbance, rarely convulsions
are the most important dose dependent
toxic effects

22.  Hepatotoxicity manifest as clinical jaundice and
multilobular necrosis. Hepatic dysfunction is
due to chemically reactive metabolite
acetylhydrazine. The drug should be
discontinued if SGOT and SGPT levels are four to
five times higher than normal in baseline value
 INH can cause haemolysis in patients deficient
in G-6PD.
 Other adverse effects include rashes, fever, acne
and arthralgia.

23. DRUG INTERACTIONS
Aluminium hydroxide inhibits INH absorption
INH inhibits Phenytoin, Carbamazepine, Diazepam and
Warfarin metabolism : may rise their blood levels.
CONTRAINDICATION
It is contraindicated in Epilepsy and Peripheral
neuritis.

25. RIFAMPICIN
 Rifampicin is a semisynthetic derivative of an
anitibiotic rifamycin produced by streptomyces
mediterranei.
 It is bactericidal to M.tuberculosis and also
active against gram-positive and gram-negative
cocci, some enteric bacteria and Chlamydia.

26. Among 1st line drugs for T.B, which of
the following is bacteriostatic
• Rifampicin
• Isoniazid
• Ethambutiol
• Pyrazinamide
• Streptomycin

27. MECHANISM OF ACTION
Rifampin binds to the β subunit of bacterial DNA
dependent RNA polymerase and there by inhibits
RNA synthesis.

28. PHARMACOKINETICS
 It is well absorbed orally.75% of the drug is
protein bound. It is metabolized in liver to an
active deacetylated metabolite which undergoes
entero hepatic circulation.
 30% of the drug is excreted through kidney.
Rifampin is distributed widely in body fluids and
tissues and penetrates inflamed meninges.

29. • It is also active against intracellular
organism. It impart orange colour to
body fluids, like saliva, urine, sputum
and tears. Its plasma half life is 2-5
hours. It should be given on empty
stomach.

30. RESISTANCE
It is either due to bacterial permeability
barrier or to a mutation of DNA dependent
RNA polymerase.
ADVERSE EFFECTS
Cutaneous syndrome- flushing, pruritus+rash
(specially on face & scalp), redness and
watering of eyes.
Flu syndrome with chills, fever, headache,
malaise and bone pain.

31. • Abdominal syndrome- nausea, vomiting,
abdominal cramps with or without diarrhea
• Other effects include.
• Hepatitis mostly in patients with preexisting
liver disease.
• haemolysis, shock and renal failure.

32. Rifabutin
• derivative of rifampin, is preferred for TB
patients coinfected with the human
immunodeficiency virus (HIV)
• who are receiving protease inhibitors (PIs) or
several of the non-nucleoside reverse
transcriptase inhibitors (NNRTIs).
• less potent inducer of CYP P450 enzymes
• adverse effects similar to those of rifampin
• can also cause uveitis, skin
hyperpigmentation, and neutropenia.

33. Rifapentine
• activity greater than that of rifampin in
animal and in vitro studies
• has longer half-life
• In combination with isoniazid,
rifapentine may be used once weekly in
patients with LTBI and in select HIV-
negative patients with minimal
pulmonary TB.

34. ETHAMBUTOL
 Ethambutol is a synthetic, water soluble, heat
stable compound. It is specific for tubercule
bacilli and bacteriostatic in nature.
MECHANISM OF ACTION
 It inhibits mycobacterial arabinosyl transferase
which helps bacterial cell wall synthesis.

35. PHARMACOKINETICS
 It is well absorbed from the gut.
 About 20% of the drug is excreted in feces and 50%
in urine in unchanged form.
 Ethambutol accumulates in renal failure, and the
dose should be reduced by half if creatinie
clearance is less than 10ml/min.
 It crosses blood brain barrier only if meninges are
inflamed. Plasma half life is 4hours.

36. ADVERSE EFFECTS
 The most common serious adverse event is
optic neuritis, resulting in loss of visual acuity
and red green color blindness. Periodic visual
acuity testing is desirable.
 Other includes, rash, fever
 hyperuricemia due to decreased renal
excretion of uric acid.

37. PYRAZINAMIDE
 Pyrazinamide is a nicotinic acid derivative. PZA
is bactericidal and has a specific action against
M.tuberculosis in intracellular acid
environment of lysosomes and phagosomes of
phagocytes and the macrophages.

38. MECHANISM OF ACTION
 Exact mechanism of action is not known. It is
proposed that it inhibits synthesis of mycolic acid
but by interacting with a different fatty acid
synthase encoding gene.
 PZA is converted to pyrazinoic acid, the active form
of drug by mycobacterial pyrazinamidase.
RESISTANCE
 Resistance my be due to impaired uptake of
pyrazinamide or mutations that impair
conversion of PZA to its active form.

39. PHARMACOKINETICS
 PZA is absorbed orally, widely distributed, has good
penetration in CSF, extensively metabolized in
liver and excreted in urine, plasma half life is 6-10
hours.
ADVERSE EFFECTS
 Adverse effects are, hepatotoxicity, arthralgia,fever,
GIT upsets and hyperuricemia.

40. Streptomycin
• an aminoglycoside antibiotic, was one of the
first effective agents for TB
• Its action appears to be greater against
extracellular organisms
• Infections due to streptomycin-resistant
organisms may be treated with kanamycin or
amikacin, to which these bacilli usually remain
susceptible.

41. Recommended doses of ATT
DRUG Daily Dose
Mg/kg for > 50 Kg
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
5 (4-6) 300 mg
10 (8-12) 600 mg
25 (20-30) 1500 mg
15(15-20) 1000 mg
15(12-18) 1000 mg

42. • KANAMYCIN AND AMIKACIN
• These drugs are aminoglycoside antibiotics.
• Kanamycin is effective against M.tuberculosis while
amikacin is effective mainly against atypical
mycobacteria.
• They are not absorbed orally,
• given I.M
• do not cross blood brain barrier and excreted in
urine.
• Ototoxicity and nephrotoxicity are common side
effects.

44. CAPREOMYCIN
• Capreomycin is a peptide protein synthesis
inhibitor antibiotic obtained from
streptomyces capreolus.
• given I.M because not absorbed orally.
• The usual dose is 15-20mg/kg with
maximum daily dose of 1Gm two to three
times a week for two to four months
• primarily reserved for the treatment of MDR-
TB
• Careful monitoring is necessary to minimize
nephrotoxicity and ototoxicity.

45. Para-aminosalicylic acid
• another one of the original TB medications.
• From the early 1950s until well into the
1960s, isoniazid, PAS, plus streptomycin was
the standard 18-month treatment regimen
• largely replaced by ethambutol for drug-
susceptible TB
• PAS remains an important component of
many regimens for MDR-TB.

46. Cycloserine
• This is an orally effective, tuberculostatic drug that
• disrupts d-alanine incorporation into the bacterial cell
wall.
• distributes well throughout body fluids, including the
CSF.
• primarily excreted unchanged in urine
• Accumulation occurs with renal insufficiency
• Adverse effects involve CNS disturbances (lethargy,
difficulty concentrating, anxiety, and suicidal tendency)
and seizures may occur.

47. Ethionamide:
• structural analog of isoniazid that also
disrupts mycolic acid synthesis
• MOA is not identical to isoniazid
• widely distributed throughout the body,
including the CSF
• Metabolism is extensive, most likely in the
liver, to active and inactive metabolites
• Adverse effects include nausea, vomiting, and
hepatotoxicity. Hypothyroidism,
gynecomastia, alopecia, impotence, and CNS
effects

48. Fluoroquinolones:
• specifically moxifloxacin and levofloxacin, have an
important place in the treatment of multidrug-
resistant tuberculosis
Macrolides
• azithromycin and clarithromycin are included in
regimens for several NTM infections including
MAC.
• Azithromycin may be preferred for patients at
greater risk for drug interactions (clarithromycin
is a both a substrate and inhibitor of
• cytochrome P450 enzymes)

49. Bedaquiline
• an ATP synthase inhibitor, is the first in a new
class of drugs approved for the treatment of
MDR-TB
• administered orally
• active against many types of mycobacteria
• may cause QT prolongation, and monitoring of
the electrocardiogram is recommended.
• agent is a CYP3A4 substrate, and administration
• with strong CYP3A4 inducers (for example,
rifampin) should be avoided

50. LINEZOLID
Is a member of the oxazolidinones, a new class of
synthetic antimicrobials. It is primarily a bacteriostatic
agent. It inhibits protein synthesis by preventing
formation of the ribosome complex that initiates
protein synthesis.
It achieves good intracellular concentrations. Its
half life is 4-6 hours. It is metabolized by oxidative
metabolism. Major adverse effects are bone marrow
suppression and irreversible peripheral and optic
neuropathy.

51. CHEMOPROPHYLAXIX
This indicated only in:
•Contacts of open cases who show recent Mantoux
conversion.
•Children with positive Mantoux and a TB patient in the family.
•Neonate of tubercular mother.
•Patients of leukemia, diabetes, silicosis, or those who are HIV
positive or are on corticosteroid therapy who show a positive
Mantoux test.
•Patients with old inactive disease who are assessed to have
received inadequate therapy.
The drugs generally used for prophylaxix has been H 300 mg
(10 mg/kg in children) daily for 6-12 months. Now because of
high incidence of H resistance, a combination of H (5 mg/kg)
and R (10 mg/kg) given for 06 months is prefe

52. ROLE OF CORTICOSTEROIDS
Corticosteroids should not be ordinarily used in
tubercular patients. They may be used under
adequate chemotherapeutic cover:
•In seriously ill patients (miliary or severe pulmonary
TB) to buy time for drugs to act.
•When hypersensitivity reactions occur to
antitubercular drugs.
•In meningeal or renal TB or pleural effusion to
reduce exudation and prevent its organization,
strictures etc.
•In AIDS patients with severe manifestations of
tuberculosis.
Corticosteroids are contraindicated in intestinal
tuberculosis.

53. THANK YOU