1. Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and causes the chronic lung infection tuberculosis. It is treated using a combination of antibiotics over a long period of time to prevent drug resistance from developing. 2. First line antibiotics include isoniazid, rifampin, pyrazinamide, and ethambutol. Isoniazid and rifampin are highly effective at killing the bacteria while pyrazinamide and ethambutol prevent resistance. Treatment involves an initial phase to relieve symptoms followed by a continuous phase to fully eliminate the bacteria. 3. Drug resistance is a major problem, requiring longer and more toxic second line treatments. Factors like non-compliance

1. TUBERCULOSIS AND ANTI-
TUBERCULAR DRUGS
G Vijay Narasimha Kumar
Asst. Professor,
Dept. of. Pharmacology
Sri Padmavathi School of Pharmacy

2. INTRODUCTION
◦ DEFINTION : Tuberculosis is a chronic granulomatous disease caused by
Mycobacterium tuberculosis.
◦ GRANULOMA : A nodule consisting of epithelioid macrophages and other
inflammatory and immune cells and matrix ( fibroblasts ) and the matrix form when
the immune system tends off and isolates an antigen.
◦ TUBERCLE : A small round grey translucent granulomatous lesion usually with central
caseation.

3. Mycobacterium tuberculosis
M. Hominis M. bovis M. avium M. vertebrae M. africanum
Mostly in humans
TUBERCULOSIS

4. Atypical mycobacterium
M. Kansasii M. scrofulaceum M. ulcerans

5. Mycobacterium tuberculosis:
◦ Atypical – due to mycolic acid ,which are long chain β hydroxylated fatty
acids
◦ Rod shaped
◦ Aerobic – requires oxygen. Hence it will lies in areas where there is more
oxygen tension
◦ Intracellular – due to tubercle the bacteria will be present in the
macrophages
less reproduction but can resist to high temperature and other
climatic conditions

6. WHY TB IS A DREADFUL DISEASE ?
REASON FOR DREADFUL DISEASE:
• Presence of Mycolic acid (90’c’ atoms
arranged in a ring like structure) in
Mycobacterium species.
• Mycolic acids
 Prevents ,resists against hydrophilic
and lipophilic antibiotics, loss of
water, transport of various substances
 Helps in evading from immune
system.
Mycolic
acids

7. Mycolic acids:
◦ Prevents action of hydrophobic antibodies
◦ Prevent bacterium from chemical damage or dehydration
◦ Evades mycobacterium from immune system
◦ Resistant to normal stains – even acid stains ( hence acid fast bacilli )
◦ Will provide favorable environment for the growth of bacteria in
macrophages

8. WHY IT CAN’T BE STAINED BY NORMAL STAINS?
Due to presence of mycolic acids and cross linked fatty acids and other lipids in
the cell wall of organisms ,making it impermeable to usual stain.
M.tuberculi in Acid fast staining
Takes up stain by carbol fuschin.
Resists decolorisation by acids and alcohol.
Don’t acquire 20 stain methylene blue
These retain carbol fuschin hence they appear red.

9. WHY TB AFFECTS ONLY LUNGS ?
M.tuberculi
Enters
Host cell
Utilizes
Cholesterol in cell membrane (Highly oxygenases amount involved in metabolism
of cholesterol into)
e-
◦ The concentrations of oxygenases greater in alveoli of lungs.Hence
Mycobacterium species majorly reside in alveoli of lungs.
◦ And as it is strict aerobe strictly thrives best in tissues with high Oxygen
tension such as in the apex of the lung.
ATP

10. SIGNS AND SYMPTOMS OF TB

13. DIAGNOSIS
Physical examination – weight loss, sputum examination
Chest X-ray
Sputum test/ culture test
Blood test
Tuberculin skin test
IFN-γ test ( Quantiferon TB-gold test )
According to RNTCP(2014) GENE EXPERT test is performed to diagnose
between MDR-TB, XDR-TB, TDR-TB.

14. ◦Tuberculin skin test:
A dose of 5 TU (tuberculin units) of PPD (0.1 ml) is injected intra
dermally and after 48-72 hours the induration(swelling) is observed.
If the swelling is <5mm – no TB
If the swelling is >5mm – TB is present
The results may be:
• False positive – due to BCG, allergens
• False negative – seen in immunocompromised patients

15. 15
Fig: Tuberculin test
Fig: Chest X-ray radiography
Showing cavity
Wheal

16. Prevention of TB
16
◦ Prevention strategies include BCG vaccination and treatment of persons with
latent tuberculosis infection who are at high risk of developing active disease.
◦ BCG was derived from an attenuated strain of M. bovis.
◦ Efficacy is between 0-80%.
◦ BCG vaccine is recommended for routine use at birth in countries with high
tuberculosis prevalence.
◦ Bacillus Calmette-Guérin (BCG)

17. Based on resistance
Susceptible MDR-TB XDR-TB
Based on their ability to undergo division
Active TB Latent TB
(may be active, slow acting, (bacteria in dormant)
intermittent, dormant)
Types of TB

18. Based on type of tissue response and age
Primary TB or Ghon’s complex or childhood TB ( infection of an
individual who has not been previously infected or immunised)
Secondary TB or Post-primary or Reinfection, or Chronic
TB(infection of an individual has been previously infected or
sensitized).

19. Active TB Latent TB
Signs and symptoms + _
Tuberculin skin test + +
Blood test + +
Sputum + _
Chest X-ray + _
Treatment + +
Transmission + +

20. ANTI TUBERCULAR DRUGS
FRIST LINE AGENTS
ISONIAZID(H)
RIFAMPICIN(R)
PYRAZINAMIDE(Z)
ETHAMBUTOL(E)
STREPTOMYCIN(S)
SECOND LINE AGENTS
*Aminoglycosides *BEDAQUILINE
KANAMYCIN *CYCLOSERINE
AMIKACIN *ETHIONAMIDES
*Macrolides *CAPREOMYCIN
AZITHROMYCIN *THIACETAMIDE
CLARITHROMYCIN
*Fluoro quinolones
LEVOFLOXACIN
MOXIFLOXACIN
*PARA AMINO SALICYLIC ACID

21. Based on Anti – TB activity
Tuberculocidal
Tuberculostatic
◦ Isoniazid
◦ Streptomycin
◦ Capromycin
◦ Ciprofloxacin
◦ Rifampicin
◦ Pyrazinamide
◦ Kanamycin
◦ Ethambutol
◦ Thiacetazone
◦ PAS
◦ Ethionamide
◦ Cycloserine

22. ◦First line drugs:- kill active bacteria, important in the early
stages of infection.
◦Second line drugs:- hinder bacterial growth.
- Strengthen treatment in the case of resistant bacteria.
- Less efficient and generally more toxic than first line drugs.

23. Isoniazid (INH)
◦ Most effective and cheapest primary anti tubercular drug.
◦ Effective in both acidic and alkaline medium
◦ Tuberculocidal for rapidly multiplying bacilli
◦ Tuberculostatic for resting bacilli
FIRST LINE AGENTS:

24. ISONIAZID (H) or ISONICOTINIC ACID HYDRAZIDE:
It is a prodrug and is converted into active form inside mycobacterium cell
MOA:
ISONIAZID(pro drug)
mycobacterial catalase peroxidase(Kat G)
Active form
forms complexes with
NADP NAD+ co-enzyme for DHFR
acyl carrier β-keto acyl
protein reductase ACP synthase Thus inhibition of DNA synthesis
(Inh A) (Kas A)
Inhibition of mycolic acid synthesis Destruction of cell wall(Tuberculocidal)

25. RESISTANCE:
Due to mutations in Kat G gene
Inh A gene
Kas A gene
ISONIAZID can kill intracellular organisms
can penetrate into caseous necrotic material (abscess)
highly active in rapidly dividing bacteria
PHARMACOKINETICS AND ADRs:
Taken orally
Absorption - good but limited when taken with high fatty diet
Distribution – very well distributed and can cross BBB and placental barrier
Metabolism – ISONIAZID N-acetyl transferase Acetyl ISONIAZID

26. Acetyl ISONIAZID
Urine Liver
excretion can accumulate &
forms free radicals
hepatotoxicity
Slow acylators – T1/2=90 min
N-Acetyl transferase hence dose adjustment is done
Fast acylators – T1/2=3 to 4 hours

27. DRUG INTERACTIONS:
It is enzyme inhibitor and inhibits cyp450 enzymes
alters metabolism of
PHENYTOIN CARBAMAZEPINE
increases their effects
Can enhance excretion of PYRIDOXINE(Vitamin B6)
peripheral neuritis, numbness
hence pyridoxine supplements(25-50mg) must be given
As it is hepatotoxic LIVER FUNCTION TESTS should be performed regularly to monitor transaminase
levels.
DOSE:
5mg/kg OD

28. Rifampicin
◦ Semisynthetic derivative of rifamycin ,
an anitibiotic obtained from streptomyces mediterranei.
◦ Highly effective tuberculocidal
◦ Acts on both intra and extracellular organisms.
◦ It is called a sterilizing agent.

29. Mechanism of action
Rifampicin
Binds with Beta subunit of DNA dependent RNA polymerase
Inhibition of m.R.N.A synthesis
Tuberculocidal effect
It cannot bind to human RNA polymerase, thus selectively destroying the bacteria.

30. oRIFAMPICIN acts on gram +ve
gram –ve
non tubercular bacteria like M. kansasii, M. avium complex
oUsed to treat MENINGITIS, LEPROSY, TB.
oRIFAMPICIN acquires resistance due to mutations in DNA dependent RNA polymerase.
PHARMACOKINETICS:
Taken orally
Food decreases absorption of RIFAMPICIN
Very well distributed (even in macrophages)
Only 10-20% of drug reaches CSF
RIFAMPICIN is a potent enzyme inducer(cyp450)
It causes hepatotoxicity but not as ISONIAZID and it is not teratogenic.

31. RIFAMPICIN can increase the metabolism of:
HIV protease inhibitors
NNRTIs
Sulfonyl ureas their T1/2 increases and hence dose
Anti epileptic drugs should be increased
QUINIDINE
WARFARIN
PROPRONOLOL
Hence in HIV patients RIFABUTIN is used which is not as potent enzyme inducer as
RIFAMPICIN
RIFAMPICIN contains metals and it undergoes enterohepatic recycling. Hence excreted
into bile and feces. As a result the urine, feces, tears and tongue turns orange red in
color.
Dose :10mg/kg OD

32. Uses TB & atypical
mycobacterial
infections
Leprosy
Prophylaxis in H.
influenza
Resistant staph
infections
Brucellosis
Pneumococcal
meningitis
To eradicate carrier
state
DOSE:
25mg/kg OD

33. Pyrazinamide
◦ Analog of nicotinamide
◦ Tuberculocidal
◦ Requires acidic pH for its
activity
◦ Mechanism of action not
clearly known.
◦ HEPATOTOXICITY is the
most common adverse effect
PYRAZINAMIDE
pyrazinamidase
PYRAZINOIC ACID
inhibits mycolic acid synthesis
Alterations in pyrazinamidase enzyme
leads to resistance.

34. CLINICAL USAGE
◦ Half life is 8-11 hrs.
◦ DOSAGE :- 50-70 mg/kg/d for twice / thrice weekly treatment regmens.
◦ Bacteriocidal & bacteriostatic. Used in both Extrapulmonary and pulmonary TB
Adverse Reactions
Hyperuricemia (precipitating gout)
Metallic state
Sulfurous eructation's
Toxic hepatitis (Not dose related)
Arthralgia, nausea, vomiting, anorexia, malaise,
Rarely photosensitivity reaction

35. ETHAMBUTOL (E):
MOA: Inhibits Arabinosyl transferase enzyme
Inhibits Arabinoglycan
Inhibits cell wall synthesis
•It can prevent emergence of resistance and can kill resistant forms.

36. ADRS:
It can cause optic neuritis – decrease visual acuity, no differentiation of red and
green colors, but reversible
It is teratogenic
DOSE:
15 mg/kg OD

37. Streptomycin
◦ Tuberculocidal
◦ Acts only against extracellular organisms
◦ Has to be given IM
◦ When used alone resistance develops.
◦ Least preferred first line drug.
DOSE:
15 mg/kg OD

38. Relative activity of first line drugs
◦ INH: potent bactericidal
◦ Rifampicin: potent bactericidal
◦Pyrazinamide: weak bactericidal
◦Ethambutol: bacteriostatic
◦Streptomycin: bactericidal
Synergistic
effect
NEVER USE A SINGLE DRUG FOR CHEMOTHERAPY IN TUBERCULOSIS, A
COMBINATION OF 2 OR MORE IS ALWAYS BETTER

39. Second line drugs in TB
◦Less effective
◦More toxic
◦Used only if organism is resistant to first line drugs
◦Ethionamide , PAS, cycloserine : bacteriostatic
◦Amikacin, capromycin, fluoroquinolones are used in Multi Drug
Resistant TB

40. THIACETAZONE (Tzn)
◦ Bacteriostatic drug.
◦ Does not add the therapeutic effect to the H,S& Z but delays resistance to these drugs.
◦ Half life is 12 hrs.
◦ No longer used due to major adverse effect is hepatitis, exfoliative dermatitis, Stevens-Jonson
syndrome.
◦ Tzn is not used in HIV patients due to incidence of serious toxicity.
◦ Dosage :- 150 mg/d in adults & 2.5mg/kg in children.

41. ETHIONAMIDE (Etm)
Blocks the synthesis of mycolic acids and it is a tuberculostatic drug.
Acts on both extra & intracellular organism.
Resistance to Etm develops rapidly.
Cross resistance with Tzm ia also seen.
Half life is 2-3 hrs.
Recommended dosage is 1g/d.
Anorexia , nausea & abdominal complaints are common.

42. CYCLOSERINE (Cys)
◦ Obtained from S.ORCHIDACEUS.
◦ It is D-alanine analogue and hence it replaces alanine which is essential for cell wall synthesis.
◦ Bacteriostatic drug.
◦ It is effective against tubercle bacilli resistant to H or S and against atypical mycobacterium.
◦ Rarely used .
◦ Dosage :- 250 mg /B.D if tolerated can be increased to 500 mg B.D

43. Macrolide antibiotics (CLARITHROMYCIN AND AZITHROMYCN)
Fluoroquinolones(CIPROFLOXACIN and OFLOXACIN):
Aminoglycosides

44. MANAGEMENT OF TB
Aims:
1. To kill the dividing bacteria in the lung lesions.
2. To kill the persisters so as to avoid relapse and ensure total cure
3. To prevent emergence of drug resistance
And based on
PATIENT
NEWLY
AFFECTED
PATIENTS
ACTIVE TB LATENT TB
PREVIOUSLY TREATED
PATIENTS AND BASED ON
DRUG SENSITIVITY TEST
LESS
SENSITIVE
MORE
SENSITIVE

45. Phases of chemotherapy
Phase I
•1-3 months
•Rapidly kills
bacilli
•Symptomatic
relief
Phase II
•4-6 months
•Eliminates
remaining
bacilli
•Prevents
relapse

46. INITIAL PHASE (2months):
• ISONIAZID (H)
• RIFAMPICIN (R)
• PYRAZINAMIDE (Z)
• ETHAMBUTOL (E)
• Pyridoxine (Vit.B6) (100mg/day)
Objectives of TB treatment:
To kill actively dividing bacteria – relieve signs and symptoms  ISONIAZID
To kill slow dividing and persistent bacteria – eradicate the disease and prevent
relapse  RIFAMPICIN, PYRAZINAMIDE
To prevent emergence of drug resistance  ETHAMBUTOL
CONTINUOUS PHASE (4months):
• ISONIAZID (H)
• RIFAMPICIN (R)
• Pyridoxine (Vit.B6)

48. Drug-Resistant TB: Definitions
◦ Mono-resistant: Resistance to a single drug
◦ Poly-resistant: Resistance to more than one drug, but not the
combination of isoniazid and rifampicin
◦ Multidrug-resistant (MDR): Resistance to at least isoniazid and
rifampicin
◦ Extensively drug-resistant (XDR): MDR plus resistance to
fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin,
kanamycin, capreomycin)

49. GROUPS OF DRUGS FOR MDR
Group 1:first-line oral agents
• pyrazinamide (Z)
• ethambutol (e)
• rifabutin (rfb)
Group 2:injectable agents
• kanamycin (Km)
• amikacin (Am)
• capreomycin (cm)
• streptomycin (S)
Group 3:fluoroquinolones
• levofloxacin (lfx)
• moxifloxacin (mfx)
• ofloxacin (ofx)
Group 4:oral bacteriostatic second-line agents
• para-aminosalicylic acid (pAS)
• cycloserine (cs)
• terizidone (Trd)
• ethionamide (eto)
• protionamide (pto)

50. GROUPS OF DRUGS FOR MDR
Group 5: Agents with unclear role in treatment of drug resistant-TB
• clofazimine (cfz)
• linezolid (lzd)
• amoxicillin/clavulanate (Amx/clv)
• thioacetazone (Thz)
• imipenem/cilastatin (ipm/cln)
• high-dose isoniazid (high-dose H)b
• clarithromycin (clr)

51. Drug treatment for MDR-TB:
According to RNTCP and WHO
Intensive phase Continuous phase
(6-9 months) (18 months)
Z – 25 mg/kg ETHIONAMIDE
E – 15 mg/kg CYCLOSERINE
AMIKACIN – 15 mg/kg OFLOXACIN/ LEVOFLOXACIN
CYCLOSERINE – 10-20 mg/kg ETHAMBUTOL
OFLOXACIN/ LEVOFLOXACIN
ETHIONAMIDE – 10-20 mg/kg

52. Drug treatment for TB in pregnancy:
• Category – I
Intensive phase Continuous phase
(2 months) (4 months)
ISONIAZID ISONIAZID
RIFAMPICIN RIFAMPICIN
PYRAZINAMIDE
• Category – II
Intensive phase Continuous phase
(2 months) (7 months)
ISONIAZID ISONIAZID
RIFAMPICIN RIFAMPICIN
ETHAMBUTOL
◦ E can be added during late but not early pregnancy. S is contraindicated.

53. Drug treatment for TB in lactating mothers:
Category – I (Acute or latent) – 6 months
Intensive phase Continuous phase
(2 months) (4 months)
H – 300 mg/day H
R – 600 mg/day R
Z – 25 mg/day
E – 25 mg/day
+ Vitamin B6 – 25-50 mg

54. Category – II (MDR-TB) – 7 months
Intensive phase Continuous phase
Z KANAMYCIN
E PAS
FLUORO QUINOLONES
CYCLOSERINE
All antiTB drugs are compatible with breastfeeding; full course should be given to the mother,
but the baby should be watched. The infant should receive BCG vaccination and isoniazid
prophylaxis

55. Drug treatment for TB in HIV patients:
Intensive phase Continuous phase
(2 months) (4-7 months)
ISONIAZID ISONIAZID
RIFABUTIN RIFABUTIN
PYRAZINAMIDE ETHAMBUTOL
ETHAMBUTOL

56. Drug treatment for MAC in HIV patients:
Intensive phase Continuous phase
(2-6 months) (6 months)
If CD4 cells <100 cells/ϻl If CD4 cells >100 cells/ϻl
CLARITHROMYCIN-500 mg OD/ CLARITHROMYCIN/AZITHROMYCIN
AZITHROMYCIN-500 mg OD ETHAMBUTOL/RIFABUTIN
ETHAMBUTOL-100 mg/day
RIFABUTIN-300 mg/day + MOXI/CIPRO/LEVOFLOXACIN-500 mg BD

57. Drug treatment for TB with Meningitis:
Intensive phase Continuous phase
(2 months) (12 months)
H-5 mg/kg/day H
R-10 mg/kg/day R
Z-25 mg/kg/day
E-15 mg/kg/day
CLARITHROMYCIN/ETHIONAMIDE – 15-20 mg/kg
PREDNISOLONE – 20-40 mg/kg