B.C.D.

A College Of Pharmacy & Technology

ASSIGNMENT
Subject – Pharmacology

Topic – Tuberculosis

Submitted By- Submitted To –

Anirban Pathak Miss. Priyanka Chakraborty

Roll No. 13
Group - A
4th Year, 7th Semester
2007-2011
Introduction –

Tuberculosis or TB (short for tubercles bacillus) is

a common and often deadly infectious disease
caused by various strains of mycobacteria, usually
Mycobacterium tuberculosis in humans.
Tuberculosis usually attacks the lungs but can also
affect other parts of the body. It is spread through
the air when people who have the disease cough,
sneeze, or spit. Most infections in humans result in
an asymptomatic, latent infection, and about one in
ten latent infections eventually progresses to active
disease which, if left untreated, kills more than 50% of its victims.

The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats,
and weight loss. Infection of other organs causes a wide range of symptoms. Diagnosis
relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as
microscopic examination and microbiological culture of bodily fluids. Treatment is
difficult and requires long courses of multiple antibiotics. Contacts are also screened and
treated if necessary. Antibiotic resistance is a growing problem in (extensively) multi-
drug-resistant tuberculosis. Prevention relies on screening programs and vaccination,
usually with Bacillus Calmette-Guérin vaccine.

One third of the world's population are thought to be infected with M. tuberculosis, and
new infections occur at a rate of about one per second. The proportion of people who
become sick with tuberculosis each year is stable or falling worldwide but, because of
population growth, the absolute number of new cases is still increasing. In 2007 there
were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8
million deaths, mostly in developing countries. In addition, more people in the developed
world are contracting tuberculosis because their immune systems are compromised by
immunosuppressive drugs, substance abuse, or AIDS. The distribution of tuberculosis is
not uniform across the globe; about 80% of the population in many Asian and African
countries test positive in tuberculin tests, while only 5-10% of the US population test
positive.

Classification

The current clinical classification system for tuberculosis (TB) is based on the
pathogenesis of the disease.
 Classification System for TB
Class Type Description
No TB exposure No history of exposure
0
Not infected Negative reaction to tuberculin skin test
History of exposure
TB exposure
1 Negative reaction to tuberculin skin test
No evidence of infection
Ghon complex
Positive reaction to tuberculin skin test
TB infection
2 Negative bacteriologic studies (if done)
No disease
Fibrocaseous cavitary lesion (usually in upper lobe of lungs)
M. tuberculosis cultured (if done)
3 TB, clinically active
Clinical, bacteriologic, or radiographic evidence of current disease
History of episode(s) of TB
or
Abnormal but stable radiographic findings
TB
4 Positive reaction to the tuberculin skin test
Not clinically active
Negative bacteriologic studies (if done)
and
No clinical or radiographic evidence of current disease
Diagnosis pending
5 TB suspect
TB disease should be ruled in or out within 3 months

Signs and symptoms

Main symptoms of variants and stages of tuberculosis, with many symptoms overlapping
with other variants, while others are more (but not entirely) specific for certain variants.
Multiple variants may be present simultaneously.

When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the
lungs. Symptoms include chest pain, coughing up blood, and a productive, prolonged
cough for more than three weeks. Systemic symptoms include fever, chills, night sweats,
appetite loss, weight loss, pallor, and often a tendency to fatigue very easily.

In the other 25% of active cases, the infection moves from the lungs, causing other kinds
of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in
immunosuppressed persons and young children. Extrapulmonary infection sites include
the pleura in tuberculosis pleurisy, the central nervous system in meningitis, the
lymphatic system in scrofula of the neck, the genitourinary system in urogenital
tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious
form is disseminated TB, more commonly known as miliary tuberculosis.
Extrapulmonary TB may co-exist with pulmonary TB as well.

Causes

The primary cause of TB, Mycobacterium tuberculosis, is a small aerobic non-motile

bacillus. High lipid content of this pathogen accounts for many of its unique clinical
characteristics. It divides every 16 to 20 hours, an extremely slow rate compared with
other bacteria, which usually divide in less than an hour. (For example, one of the fastest-
growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since
MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-
positive bacterium. However, if a Gram stain is performed, MTB either stains very
weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content
of its cell wall. MTB can withstand weak disinfectants and survive in a dry state for
weeks. In nature, the bacterium can grow only within the cells of a host organism, but M.
tuberculosis can be cultured in vitro.

Mechanism
Transmission

When people suffering from active pulmonary TB cough, sneeze, speak, or spit, they
expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze can release up
to 40,000 droplets. Each one of these droplets may transmit the disease, since the
infectious dose of tuberculosis is very low and inhaling less than ten bacteria may cause
an infection.

People with prolonged, frequent, or intense contact are at particularly high risk of
becoming infected, with an estimated 22% infection rate. A person with active but
untreated tuberculosis can infect 10–15 other people per year. Others at risk include
people in areas where TB is common, people who inject drugs using unsanitary needles,
residents and employees of high-risk congregate settings, medically under-served and
low-income populations, high-risk racial or ethnic minority populations, children exposed
to adults in high-risk categories, patients immunocompromised by conditions such as
HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving
these high-risk clients.

Transmission can only occur from people with active — not latent — TB. The
probability of transmission from one person to another depends upon the number of
infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of
exposure, and the virulence of the M. tuberculosis strain. The chain of transmission can,
therefore, be broken by isolating patients with active disease and starting effective anti-
tuberculous therapy. After two weeks of such treatment, people with non-resistant active
TB generally cease to be contagious. If someone does become infected, then it will take
at least 21 days, or three to four weeks, before the newly infected person can transmit the
disease to others. TB can also be transmitted by eating meat infected with TB.
Mycobacterium bovis causes TB in cattle.

Pathogenesis

About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent
TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent
infection will progress to TB disease. However, if untreated, the death rate for these
active TB cases is more than 50%.

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they
invade and replicate within the endosomes of alveolar macrophages. The primary site of
infection in the lungs is called the Ghon focus, and is generally located in either the upper
part of the lower lobe, or the lower part of the upper lobe. Bacteria are picked up by
dendritic cells, which do not allow replication, although these cells can transport the
bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to
other tissues and organs where secondary TB lesions can develop in other parts of the
lung (particularly the apex of the upper lobes), peripheral lymph nodes, kidneys, brain,
and bone. All parts of the body can be affected by the disease, though it rarely affects the
heart, skeletal muscles, pancreas and thyroid.

Tuberculosis is classified as one of the granulomatous inflammatory conditions.

Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that
aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages.
The granuloma functions not only to prevent dissemination of the mycobacteria, but also
provides a local environment for communication of cells of the immune system. Within
the granuloma, T lymphocytes secrete cytokines such as interferon gamma, which
activates macrophages to destroy the bacteria with which they are infected. Cytotoxic T
cells can also directly kill infected cells, by secreting perforin and granulysin.

Diagnosis

Tuberculosis is diagnosed definitively by identifying the causative organism

(Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When
this is not possible, a probable - although sometimes inconclusive - diagnosis may be
made using imaging (X-rays or scans) and/or a tuberculin skin test (Mantoux test).

The main problem with tuberculosis diagnosis is the difficulty in culturing this slow-
growing organism in the laboratory (it may take 4 to 12 weeks for blood or sputum
culture). A complete medical evaluation for TB must include a medical history, a
physical examination, a chest X-ray, microbiological smears, and cultures. It may also
include a tuberculin skin test, a serological test. The interpretation of the tuberculin skin
test depends upon the person's risk factors for infection and progression to TB disease,
such as exposure to other cases of TB or immunosuppression.

Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin

test, which yields a delayed hypersensitivity type response to an extract made from M.
tuberculosis. Those immunized for TB or with past-cleared infection will respond with
delayed hypersensitivity parallel to those currently in a state of infection, so the test must
be used with caution, particularly with regard to persons from countries where TB
immunization is common. Tuberculin tests have the disadvantage of producing false
negatives, especially when the patient is co-morbid with sarcoidosis, Hodgkins
lymphoma, malnutrition, or most notably active tuberculosis disease. The newer
interferon release assays (IGRAs) overcome many of these problems. IGRAs are in vitro
blood tests that are more specific than the skin test. IGRAs detect the release of interferon
gamma in response to mycobacterial proteins such as ESAT-6. These are not affected by
immunization or environmental mycobacteria, so generate fewer false positive results.
There is also evidence that the T-SPOT.TB IGRA is more sensitive than the skin test.
Diagnosis of TB has also been done with use of various radiotracers using nuclear
medicine methods, which not only detects but also locates tubercular infection.

New TB tests are being developed that offer the hope of cheap, fast and more accurate
TB testing. These include polymerase chain reaction assays for the detection of bacterial
DNA. The development of a rapid and inexpensive diagnostic test would be particularly
valuable in the developing world.

Prevention

Map showing the 22 high-burden countries (HBC) that according to WHO account for
80% of all new TB cases arising each year. The Global Plan is especially aimed at these
countries.

TB prevention and control takes two parallel approaches. In the first, people with TB and
their contacts are identified and then treated. Identification of infections often involves
testing high-risk groups for TB. In the second approach, children are vaccinated to
protect them from TB. No vaccine is available that provides reliable protection for adults.
However, in tropical areas where the levels of other species of mycobacteria are high,
exposure to nontuberculous mycobacteria gives some protection against TB.

The World Health Organization (WHO) declared TB a global health emergency in 1993,
and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to
save 14 million lives between 2006 and 2015. Since humans are the only host of
Mycobacterium tuberculosis, eradication would be possible. This goal would be helped
greatly by an effective vaccine.

Vaccines

Many countries use Bacillus Calmette-Guérin (BCG) vaccine as part of their TB control
programmes, especially for infants. According to the WHO, this is the most often used
vaccine worldwide, with 85% of infants in 172 countries immunized in 1993. This was
the first vaccine for TB and developed at the Pasteur Institute in France between 1905
and 1921. However, mass vaccination with BCG did not start until after World War II.
The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in
children is greater than 80%; its protective efficacy for preventing pulmonary TB in
adolescents and adults is variable, ranging from 0 to 80%.

In South Africa, the country with the highest prevalence of TB, BCG is given to all
children under age three. However, BCG is less effective in areas where mycobacteria are
less prevalent; therefore BCG is not given to the entire population in these countries. In
the USA, for example, BCG vaccine is not recommended except for people who meet
specific criteria:

• Infants or children with negative skin test results who are continually exposed to
untreated or ineffectively treated patients or will be continually exposed to
multidrug-resistant TB.
• Healthcare workers considered on an individual basis in settings in which a high
percentage of MDR-TB patients has been found, transmission of MDR-TB is
likely, and TB control precautions have been implemented and were not
successful.

BCG provides some protection against severe forms of pediatric TB, but has been shown
to be unreliable against adult pulmonary TB, which accounts for most of the disease
burden worldwide. Currently, there are more cases of TB on the planet than at any other
time in history and most agree there is an urgent need for a newer, more effective vaccine
that would prevent all forms of TB—including drug resistant strains—in all age groups
and among people with HIV.

Several new vaccines to prevent TB infection are being developed. The first recombinant
tuberculosis vaccine rBCG30, entered clinical trials in the United States in 2004,
sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). A 2005
study showed that a DNA TB vaccine given with conventional chemotherapy can
accelerate the disappearance of bacteria as well as protect against re-infection in mice; it
may take four to five years to be available in humans. A very promising TB vaccine,
MVA85A, is currently in phase II trials in South Africa by a group led by Oxford
University, and is based on a genetically modified vaccinia virus. Many other strategies
are also being used to develop novel vaccines, including both subunit vaccines (fusion
molecules composed of two recombinant proteins delivered in an adjuvant) such as
Hybrid-1, HyVac4 or M72, and recombinant adenoviruses such as Ad35. Some of these
vaccines can be effectively administered without needles, making them preferable for
areas where HIV is very common. All of these vaccines have been successfully tested in
humans and are now in extended testing in TB-endemic regions. To encourage further
discovery, researchers and policymakers are promoting new economic models of vaccine
development including prizes, tax incentives and advance market commitments.

Treatment

Treatment for TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult,
due to the unusual structure and chemical composition of the mycobacterial cell wall,
which makes many antibiotics ineffective and hinders the entry of drugs. The two
antibiotics most commonly used are rifampicin and isoniazid. However, instead of the
short course of antibiotics typically used to cure other bacterial infections, TB requires
much longer periods of treatment (around 6 to 24 months) to entirely eliminate
mycobacteria from the body. Latent TB treatment usually uses a single antibiotic, while
active TB disease is best treated with combinations of several antibiotics, to reduce the
risk of the bacteria developing antibiotic resistance. People with latent infections are
treated to prevent them from progressing to active TB disease later in life.

Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary
resistance occurs in persons who are infected with a resistant strain of TB. A patient with
fully susceptible TB develops secondary resistance (acquired resistance) during TB
therapy because of inadequate treatment, not taking the prescribed regimen appropriately,
or using low quality medication. Drug-resistant TB is a public health issue in many
developing countries, as treatment is longer and requires more expensive drugs. Multi-
drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective
first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is
also resistant to three or more of the six classes of second-line drugs.

The DOTS (Directly Observed Treatment Short-course) strategy of tuberculosis

treatment recommended by WHO was based on clinical trials done in the 1970s by
Tuberculosis Research Centre, Chennai, India. The country in which a person with TB
lives can determine what treatment they receive. This is because multidrug-resistant
tuberculosis is resistant to most first-line medications, the use of second-line
antituberculosis medications is necessary to cure the patient. However, the price of these
medications is high; thus poor people in the developing world have no or limited access
to these treatments.

Reference
• http://en.wikipedia.org/wiki/ Tuberculosis

• Wilson and Grisvold’s ; “Text Book of

Organic Medicinal And Pharmaceutical
Chemistry” ; 11th Edition

• K.D.Tripathi ; “Essentials Of Medicinal

Pharmacology” ; 6th Edition

• http://whoindia.org/en/Section3/Section12
3.htm