2. INTRODUCTION
a chronic granulomatous disease caused by
◦ DEFINTION : Tuberculosis is
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.
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:
atoms
• Presence
arranged
of Mycolic acid (90 C
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)
◦ The concentrations of
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.
e- ATP
oxygenases greater in alveoli of lungs.Hence
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
• *PPD : Purified Protein Derivative.
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
Latent TB
(bacteria in dormant)
Active TB
(may be active, slow acting,
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)
TB or Post-primary or Reinfection, or Chronic
of an individual has been previously infected or
Secondary
TB(infection
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
*BEDAQUILINE
*CYCLOSERINE
*ETHIONAMIDES
*CAPREOMYCIN
*THIACETAMIDE
*Aminoglycosides
KANAMYCIN
AMIKACIN
*Macrolides
AZITHROMYCIN
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)
◦ Isoniazid, also known as isonicotinic acid hydrazide (INH), is
an antibiotic used for the treatment of tuberculosis.
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. Mechanism of action
Isoniazid is a prodrug that inhibits the formation of the mycobacterial cell wall. Isoniazid must be
activated by KatG, a bacterial catalase-peroxidase enzyme in Mycobacterium tuberculosis.
KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples
with NADH to form the nicotinoyl-NAD adduct. This complex binds tightly to the enoyl-acyl carrier
protein reductase InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty
acid synthase. This process inhibits the synthesis of mycolic acids, which are required
components of the mycobacterial cell wall.
25. 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
Thus inhibition of DNA synthesis
acyl carrier
protein reductase
(Inh A)
β-keto acyl
ACP synthase
(Kas A)
Inhibition of mycolic acid synthesis Destruction of cell wall(Tuberculocidal)
26. 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
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
27. Rifampicin
◦ Semisynthetic derivative of rifamycin ,
an anitibiotic obtained from Amycolatopsis
rifamycinica
previously known as Amycolatopsis
mediterranei and Streptomyces
mediterranei)
◦ Highly effective tuberculocidal
◦ Acts on both intra and extracellular
organisms.
28. 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.
29. The DNA dependent RNA
polymerase helps in the
transcription of DNA into RNA..
Transcriptio
Translation
30.
31. Uses TB & atypical
mycobacterial
infections
Leprosy
Prophylaxis in H.
influenza
Resistant staph
infections
Brucellosis
Pneumococcal
meningitis
To eradicate carrier
state
DOSE:
25mg/kg OD
32. Pyrazinamide
◦ Analog of nicotinamide
◦ Chemically it is Pyrazine-2-
caboxamide
◦ Tuberculocidal
Requires s acidic pH for
its activity
◦ HEPATOTOXICITY is the
most common adverse effect
34. ETHAMBUTOL (E):
Ethambutol is an ethylenediamine derivative that is ethane-1,2-
diamine in which one hydrogen attached to each of the nitrogens is
sutstituted by a 1-hydroxybutan-2-yl group.
It is a bacteriostatic
antimycobacterial drug, effective
against Mycobacterium tuberculosis
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. Streptomycin
◦ Tuberculocidal
◦ Acts only against extracellular organisms
◦ Has to be given IM
MOA:Inhibition of protein synthesis
of mycobacteria in the ribosome
It is an aminoglycoside antibiotic with a central aldose sugar-streptose
connected to an amino sugar N-methyl-l-glucosamine and aglycone-
streptidine containing two guanidine groups via O-glycosidic linkages
37. Second line drugs in TB
◦Less effective
◦More toxic
◦Used only if organism is resistant to first line drugs
38. ETHIONAMIDE (Etm)
Blocks the synthesis of mycolic acids and it is a tuberculostatic drug.
Acts on both extra & intracellular organism.
39. CYCLOSERINE (Cys)
◦ Obtained from S.ORCHIDACEUS. Bacteriostatic drug.
◦ It is D-alanine analogue and hence it replaces alanine which is essential for cell wall synthesis.
40. The mechanism of action has been postulated to be inhibition of folic
acid synthesis
Para Amino Salicylic Acid
42. Capreomycin is an antibiotic which is given in combination with
other antibiotics for the treatment of tuberculosis. Capreomycin was
discovered from Streptomyces capreolus
Inhibit protein synthesis by binding to the 70S ribosomal unit
