Langhans type cell means peripherally arranged nuclei in the form of horse shoe shaped or ring shaped. Caseation necrosis is charaterized by cheesy appearance and high lipid content.
Tuberculoosis and antitubercular drugs
G Vijay Narasimha Kumar
Dept. of. Pharmacology
Sri Padmavathi School of Pharmacy
• A chronic bacterial infection caused by Mycobacterium
tuberculosis, usually characterized pathologically by the
formation of granulomas. The most common site of
infection is the lung, but other organs such as may be
• Other common names included “wasting disease” and the
• TB is caused by Mycobacterium species mainly by
– Mycobacterium tuberculi which is aerobic atypical rod shaped
• Other strains which causes TB are
– M.bovis ( Commonly caused by consumption of
• Less common strains which causes TB are
• Less pathogenic strains are
• Non pathogenic strains are M.smegmatis
• M.tuberculi also called as Koch’s bacilli or Acid Fast
WHY TB IS A DREADFUL DISEASE ?
• Presence of Mycolic
acid (90’c’ atoms
arranged in a ring like
• Mycolic acids
antibiotics, loss of
Helps in evading
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 satin by carbol fuschin.
Resists decolorisation by acids and alcohol.
Don’t acquire 20 stain methylene blue
These retain carbol fuschin hence they
WHY TB AFFECTS ONLY LUNGS ?
Cholesterol in cell membrane (Highly oxygenases amount involved in
metabolism of cholesterol into)
• 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
• TB is spread through the air from one person to
– Inhalation( cough droplets)
– Ingestion (self-swallowing of infected
– Inoculation(organisms into tissue which may
occur from infected postmortem tissue),
– Trans placental routes( Leads to congenital
types of tuberculosis
• Based on anatomical site
– PULMONARY TB (lungs)
– MILIARY TB (Liver, kidney spleen brain)
• Based on presence of signs and symptoms
– Active TB (only shows signs and symptoms).
– Latent TB (signs and symptoms are
• 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).
• When ever the Mycobacterium tuberculi enters body. As it is
strictly aerobic it resides in alveoli of lungs.
• In alveoli, they will be engulfed by alveolar macrophages and with in
macrophages they will be converted into phagosome
• Phagosome should convert into phagolysosome but the M.tuberculi inhibits
the fusion of phagosome with lysosome there by no formation of
• Thus the mycobacterium tuberculosis antigen becomes “Difficut to
However, a very few no.of macrophages/some cells can process the
The APC containing expressed MTB antigen enters lymphatic system and
reaches lymphatic organs.
Activation of TH1cells(Cell mediated Immunity)
Activation of INF-γ on endothelial cells of blood vessels
Activation of Monocyte Adherent Protein (MAP) on endothelium and adherence
of monocyte to MAP
Squeezing of monocytes from blood to site of injury. Thus monocytes
entered into site of injury becomes Macrophages and increases in number.
Macrophages engulf Mycobacterium tuberculosis at site of injury.Due to
inhibition of Fusion of Phagolysosome, Macrophages are unable to digest
Granuloma (Agroup of cluster of epitheloid cells surrounded by rim of
lymphocytes around them)
Some of macrophages form Multinucleated giant cells by fusion of adjacent
cells (Langhans type)
Surrounding the epithelioid cells and giant cells there is a zone of
lymphocytes,plasma cells, and fibroblasts. This lesion at this stage is called
Hard tubercle due to absence of central necrosis.
Within 10-14 days, the centre of the cellular mass undergoes into
CASEATION NECROSIS(microscopically necrosis is structureless esinophilic
and granular material with debris) . This stage is called soft tubercle.
Wide spread of Soft tubercle over various parts of alveoli and lungs causes
These soft tubercle wide spread into various parts of the body like kidney
spleen, liver and bones etc.,.
In those freshly infected parts Mycobacterium tuberculi diffuse out of Soft
tubercle and infects which leads to formation of new granulomas.
Newly formed granulomas damages tissue and degenerates tissue surrounding
Extensive spread and damage of various parts of body occurs. This condition is
called MILIARY TUBERCULOSIS.
When infected person coughs or sneezes, the granulomas that may be present
in sputum comes in contact with air.
Lymphocytes, fibroblasts surrounding the cluster of epitheloid cells become
inactivated. And Mycobacterium tuberculi gets free from epitheloid cells
Comes in contact with another person
New person develops TB
• Chest X- ray
• Laboratory diagnosis
– Sputum examination for AFB
– Complete haemogram (lymphocytosis and raised ERR).
– Culture and drug sensitivity tests using BACTEC radiometric method (
this method used to detect live bacilli) .
– D.N.A probe technology
– Nucleic acid amplification test- PCR
– ELISA testing for IgG antibodies ( It denotes only past infection , but
not useful as diagnostic aid).
– Drug susceptibility testing to anti-TB drugs.
– Gene Xpert (to differentiate 10 /Multi drug resistant TB)
– Fine needle aspiration cytology of an enlarged peripherallymph node is
quite helpful for confirmation of diagnosis
– INF- ɣTESTS
• Quantiferon TB gold intube
• Sputum collection
• Tuberculin test
• A presumptive diagnosis is commonly based on
the finding of AFB on microscopic examination
of a clinical sample (e.g., sputum/pus).
• When this is not possible, a probable diagnosis
may be made using imaging (X-ray/scans) and/or
a tuberculin skin test (Mantoux test).
• Tuberculin skin test, which yields a delayed
hypersensitivity type response (a small, raised,
blanched wheal) to an extract made from M.
tuberculosis (purified protein derivative; PPD).
• TUBERCULIN SKIN TEST: Purified protein
derivative (PPD), 0.1ml Intradermally, conc.
0.002mg/ml. If a raised bump of more than 5
mm (0.2 in) appears at the site 48 hours later,
the test may be positive.
•This test can often indicate disease when there is
none (false positive). Also, it can show no disease
when you may in fact have TB (false negative).
• 0–4 mm Negative
• 5–9 mm Doubtful (may be due to atypica
• 10 mm or more Positive
• In HIV infected individuals, 5 mm is considered
• Tuberculin negative patients should be
vaccinated with BCG.
• False-negative tuberculin tests (i.e. negative skin
tests occurring in patients with tuberculosis).
Prevention of TB
• 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.
• Efficacy is between 0-80%.
• BCG vaccine is recommended for routine use at
birth in countries with high tuberculosis
• Bacillus Calmette-Guérin (BCG)
FIRST LINE AGENTS
Catalase peroxidase (enzyme of
InH a Kas a dihydrofolate
Inhibition of Inhibition of
Mycolic acid DNA synthesis
• Resistance :
– Mycobacteria may develops
resistance towards H due to
change in genes coding for
– Alteration in Kas a and Inh a
and in structure of efflux
pumps of bacteria.
– Orally well absorbed
– Well distributed
– Metabolized in Liver by
– Based on acylation
• Slow acetylators (Half
• Fast acetylators( Half
– Excreted through urine
• Adverse effects:
– GI disturbances,
– Peripheral Neuritis
– Hypersensitivity reactions
Mechanism of action
Binds with Beta subunit of
DNA dependent RNA
Inhibition of m.R.N.A
– Orally well absorbed
– High protein bound
– Distributed to all parts
– Metabolized in liver into desacetyl
rifampicin which undergoes entero-
– Excreted largely in feces and small in
– Enzyme inducer for
• HIV protease inhibitors
• Azole antifungals,Sulphonyl
• ADVERSE EFFECTS:
– Patients with hepatic disease are prone
– Allergic reactions-Pruritis
– GI disturbances
– Flulike symptoms
MECHANISM OF ACTION
mycolic acid synthesis Disrupts
• Pyrazinoic acid Highly effective in
acid environment and inflammatory
– Rapidly absorbed from GI tract
– It is widely distributed in the
body and achieves a concentration
in the CSF equal to the plasma
– Deaminated in theliver.
– Degradation products and he free
drug are eliminated in urine
• ADVERSE EFFECTS:
– Hyperuricemia (precipitating
– Metallic state
– Sulfurous eructation's
– Toxic hepatitis (Not dose related)
– Rarely photosensitivity reaction
• Used in both Extrapulmonary and
MECHANISM OF ACTION
Inhibits Arabinosyl transferase
Inhibits Synthesis of ARABINO
Inhibits cell wall synthesis
• Only tuberculostatic among all first line
Anti tubercular agents.
• Suppress the emergence of resistance
• Hastens sputum conversion
– 70% is absorbed
– Penetrates into erythrocytes, gets
deposited, and released into
– 50% of oral dose excreted
unchanged in urine with in 24h
– 15% excreted in the form of two
– Accumulates in presence of renal
• ADVERSE EFFECTS:
– Retrobulbular optic neuritis on
prolonged therapy which results in
decrease visual acuity.
– Others are
• If any visual disturbances are seen in
the patient,Ethambutol should be
removed from patient’s regimen
MECHANISM OF ACTION
Binds to 30S subuint of
Which results in production
– Not absorbed orally and must be
given in IM. Well absorbed when
instilled in intrapleurally
– It doesn’t cross BBB. However,
high concentrations are seen in
CSF during meningeal
– It is mainly concentrated in
kidneys, liver, and skeletal
– It crosses Placental barrier,
– Excreted unchanged by GFR. And
approximately 50-60% of drug is
eliminated in urine in active form
• ADVERSE EFFECTS:
– Pain at the site of injection
– 8th cranial nerve damage
– Neuromuscular blockade
– Nephrotoxicity and ototoxicity
– Super infections with
Staphylococcus aureus and
• Because of its low cost and
efficacy combination with H it
was once used in 1st line drugs
• It is orally active , rapidly
diffuses into various body
tissues ,Partly metabolized in
liver and about 40% excreted
unchanged in urine with t1/2 12h.
• It is no longer used now because
of its Exfoliative dermatitis
ototoxicity and life-threatening
PARA-AMINO SALICYLIC ACID(PAS)
• It is chemically as well as in
mechanism of action related to
Sulfonamides.It is not active against
other bacteria and the reason may be
due to the difference in the affinity
of folate synthetase of TB and other
• Absorbed completely by oral route
and distributed all over the body
except CSF,about 50% PAS is
aceylated and competes with
acetylation of H- Prolongs its
t1/2.Excreted rapidly by Glomerular
filtration and tubular secretion.
• Patient acceptibility is poor because
of frequent anorexia, nausea and
epigastric pain and other adverse
effects are blood dyscrasias, fever
SECOND LINE AGENTS
These alternative drugs that are useful in cases of resistance to 1st line drugs
• MECHANISM OF ACTION :It is
D-alanine analogue and hence it
replaces alanine which is essential
for cell wall synthesis.
• PHARMACOKINETICS: Rapidly
absorbed from gut,distributed
through out the body (csf and
plasma concentrations are equal in
meningitis condition).50% of orally
administered dose gets excreted
in urine in unchanged form and
65% is excreted by kidneys within
• Broad spectrum antibiotic and it is
• It is effective against tubercle
bacilli resistant to H or S and
against atypical mycobacterium.
• ADVERSE EFFECTS:
– Peripheral neuropathy,
– Delusions, Nervousnessetc.,.
• MECHANISM OF ACTION:
Blocks the synthesis of
mycolic acids and it is a
ABSORPTION is similar to H,
Metabolized in liver and only
1% excreted unchanged in
• Because of its Intense gastric
irritation and neurological
toxicity(optic and peripheral
neuritis) and hepatotoxicity, it
is rarely used, as in
recommended dose of 1mg/kg.
• ADVERSE EFFECTS:
• GI disturbances
• Toxic hepatitis
• The fluoroquinolones are useful
new addition to the anti
sparfloxacin are active against
M.tuberculosis as well as
• They penetrate cells and kill
mycobacteria lodged in
• Because of their good
tolerability,they are being
combination regimens against
MDR TB and MAC infection
• The generally employed doses
are ciprofloxacin 1500 mg/ day
and ofloxacin 800mg/ day in 2
divided doses. Sparfloxacin is
more active against
mycobacteria in vitro, but has
been used clinically to a lesser
• These newer macrolide
antibiotics are most active
mycobacteria including MAC,
M. fortuitum, M. Kansasii
and M. marinum.
• Clarithromycin has been
used to a greater extent
because its MIC values are
lower, but azithromycin may
be equally efficacious due to
its higher tissue and
• combination with other
drugs. In AIDS patients,
life-long therapy is
MANAGEMENT OF TB
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
treatment is given
ACTIVE TB LATENT TB
PATIENTS AND BASED ON
DRUG SENSITIVITY TEST
FOR NEWLY INFECTED PATIENTS
FOR PREVIOUSLY TREATED PATIENTS WITH LOW
RESISTANCE TO DRUGS
HRZ + Pyridoxine
MULTI DRUG RESISTANT OR HIGHLY
For H resistance: R+Z+E for 12Months
For R resistance: H+Z+E for 12Months
For both H+R resistance: Z+E+S(Et)+CIROFLOXACIN(OR OFLOXACIB
OR LEVOFLOXACIN),for 12-18 Months
DOT’s REGIMEN OF RNTCP(REVISED NATIONAL TUBERCULOSIS
CONTROL PROGRAMME) -1997
TB in special population
• TUBERCULOSIS IN PREGNANT WOMEN:
• H, R and Z to be safe to the foetus and
recommend the standard 6 month (2HRZ
+ 4HR) regimen for pregnant women with
TB. E can be added during late but not
early pregnancy. S is contraindicated.
• India, it is advised to avoid Z, and to
treat pregnant TB patients with 2 HRE +
7HR (total 9 months). Treatment of TB
should not be withheld or delayed
because of pregnancy.
• TREATMENT OF BREASTFEEDING WOMEN :
• 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
• In case of M. tuberculosis infection, drugs used are the same as in non-HIV cases,
but the duration is longer and at least 4 drugs are used.
• Initial therapy with 2 month HRZE is started immediately on the diagnosis of TB,
and is followed by a continuation phase of HR for 7 months (total 9 months).
• Alternatively, 3 drugs (HRE) are given for 4 months in the continuation phase.
Pyridoxine 25-50 mg/ day is routinely given along with H to counteract its
neurological side effects, which are more likely in AIDS patients.
• MDR-TB in HIV-AIDS patients should be treated for a total of 18-24
months or for 12 months after sputum smear negativity.
Tb in hiv
Treatment of TB in MAC
• Mycobacterium avium complex (MAC) infection is common in
HIV-AIDS patients, particularly when the CD4 count drops to <
• Clarithromycin/ azithromycin are the most active drugs against
MAC. A favoured regimen consists of an intensive phase of at
least 4 drugsclarithromycin/ azithromycin + ethambutol
rifabutin + one FQ / clofazimine/ ethionamide given for 2-6
months (duration is response based) .
• Followed by 2 drug maintenance phase with clarithromycin/
azithromycin + ethambutol/ one FQ/ rifabutin for at least 1 2
months or eYen lifelong.
• However, any additional benefit of the initial 4 drug intensive
phase is unproven. Clarithromycin inhibits the metabolism of