Tuberculosis is caused by Mycobacterium tuberculosis and typically affects the lungs. It remains a major global health problem, especially in poorer countries. Risk factors include malnutrition, inadequate healthcare, poverty, and conditions that weaken the immune system. It is transmitted via airborne droplets from the lungs of infected individuals. Diagnosis involves tests like the Mantoux test and culturing sputum samples. Treatment requires a multi-drug regimen over a long period to prevent resistance. First-line drugs include isoniazid, rifampicin, pyrazinamide, and ethambutol.

1. TUBERCULOSIS
T. SOUJANYA
16DC1T0021
PHARM. D

2. CONTENT:
• Definition
• Epidemiology
• Etiology
• Types of tuberculosis
• Risk factors
• Mode of transmission
• Pathophysiology of tuberculosis
• Diagnostic tests
• Clinical features
• Signs and symptoms
• Management of tuberculosis

3. DEFINITION:
Tuberculosis is a communicable chronic granulomatous disease
caused by “Mycobacterium tuberculosis”. It usually involves the lungs
but may affect any organ or tissue in the body. Typically the centres of
tubercular granulomas undergo “causeous necrosis”.

4. EPIDEMIOLOGY:
Inspite of great advances in chemotherapy and immunology,
tuberculosis still continues to be worldwide in distribution, more
common in poorer countries of Africa, Latin America and Asia. Other
factors contributing to higher incidence of tuberculosis are
malnutrition, inadequate medical care, poverty, crowding, chronic
debilitating conditions like uncontrolled diabetes, alcoholism and
immunocompromised states like AIDS.

5. ETIOLOGY:
TB is caused by tubercle bacilli, which belong to the genus
Mycobacterium. Mycobacterium species include:
1. M.tuberculosis complex: M.tuberculosis, M.bovis, M.africanum.
2. Mycobacteria other than tuberculosis: Around 15 are recognised as
pathogenic to humans and some cause pulmonary disease
resembling TB. They have been found in soil, milk and water. They
are also referred to as “atypical mycobacteria”.
3. Mycobacterium leprae, the cause of leprosy.

6. TYPES OF TUBERCULOSIS:
1. PULMONARY TUBERCULOSIS:
It mainly involves in lungs and pleura (85% of all TB cases). It is again classified into:
• Primary tuberculosis
• Secondary tuberculosis
2. EXTRA-PULMONARY TUBERCULOSIS: It is classified into:
• Lymph node (peripheral) tuberculosis
• Genito-urinary tuberculosis
• Skeletal tuberculosis
• Meningeal tuberculosis
• Gastrointestinal tuberculosis
• Disseminated/miliary tuberculosis
• Pericardial tuberculosis

7. TYPES OF PULMONARY TUBERCULOSIS:
Lungs are the main organs affected in tuberculosis. The infection
with tubercle bacilli is of two main types:
1. Primary tuberculosis
2. Secondary tuberculosis

8. 1. PRIMARY TUBERCULOSIS:
The infection of an individual who has not been previously infected
or immunised is called “primary tuberculosis” or “Ghon‘s complex” or
“childhood tuberculosis”.
Primary complex or Ghon’s complex is the lesion produced at the
portal of entry with foci in the draining lymphatic vessels and lymph
nodes. The most commonly involved tissues for primary complex are
lungs and hilar lymph nodes. The incidence of disseminated form of
progressive primary tuberculosis is particularly high in
immunocompromised host.

9. 2. SECONDARY TUBERCULOSIS:
The infection of an individual who has been previously infected or
sensitized is called “secondary or post-Primary or reinfection or chronic
tuberculosis”. The infection may be aquired from:
• Endogenous source such as reactivation of dormant primary complex
• Exogenous source such as fresh dose of reinfection by tubercle bacilli.

10. RISK FACTORS:
The following are some of the risk factors of tuberculosis:
1. Low socio-economic status
2. Crowded living conditions
3. Disease that weakens immune system like HIV
4. Person or immunosuppressants like steroid health care workers
5. Migration from a country with high number of cases
6. Alcoholism
7. Recent tubercular infection (within last 2 years)

11. MODE OF TRANSMISSION:
Human beings acquire infection with tubercle bacilli by one of the
following routes:
1. Inhalation
2. Ingestion
3. Inoculation of tissue
4. Transplacental route

12. PATHOPHYSIOLOGY OF TUBERCULOSIS:
The sequence of events from inhalation of the infectious inoculum to
containment of primary focus can be stated as following:
A) Primary pulmonary tuberculosis (0-3 weeks):
The virulent strains of mycobacteria gain entry into the macrophage
endosomes, the organisms are able to inhibit normal microbicidal response
by manipulation of endosomal pH and arrest of endosomal maturation. The
end result of this “endosomal manipulation” is impairment of effective
phagolysosome formation and unhindered mycobacterial proliferation. Thus,
the earliest phase of primary tuberculosis (<3 weeks) in the non-sensitized
individual is characterised by bacillary proliferation within the pulmonary
alveolar macrophages and air spaces, with resulting bacteremia and seeding
of multiple sites. Most persons at this stage are asymptomatic or have a mild
flu like illness.

14. Contd...
B) Primary pulmonary tuberculosis (>3 weeks):
1. The development of cell mediated immunity occurs approximately 3
weeks after exposure. Processed mycobacterial antigens reach the
draining and are presented in a major histocompatibility class-II context
by dendritic cell macrophages to CD4
+ T-cells. Under the influence of
macrophage-secreted IL-12, CD4
+ T-cells of the TH1 subset are
generated, capable of secreting IFN-gamma.

15. Contd...
2. IFN-gamma released by the CD4
+ T-cells of the TH1 subset is crucial in
activating macrophages. Activated macrophages, in turn, release a
variety of mediators with important down-stream effects, including:
a) Secretion of TNF
b) Expression of inducible nitric oxide synthase (iNOs) gene
c) Generation of reactive oxygen species
3. Defects in any of the steps of a TH1 response (including IL-12, IFN-
gamma, TNF or nitric oxide production) result in poorly formed
granulomas, absence of resistance and disease progression.

17. DIAGNOSTIC TESTS:
The following are some of the tests used in the diagnosis of
tuberculosis:
1. Mantoux test/Tuberculin sensitivity test
2. Acid fast bacilli (AFB) test
3. Mycobacterial culture
4. PCR (Polymerase chain reaction) test
5. Radiographic procedures

18. CLINICAL FEATURES:
1. Referable to lungs: such as productive cough, may be with
haemoptysis, pleural effusion, dyspnoea, orthopnoea etc. Chest X-
ray shows typical apical changes like pleural effusion, nodularity and
miliary or diffuse infiltrates in the lung parenchyma.
2. Systemic features: such as fever, night sweats, fatigue, loss of
weight and appetite. Long-standing and untreated cases of
tuberculosis may develop systemic secondary amyloidosis. Causes
of death in primary tuberculosis are usually pulmonary
insufficiency, pulmonary haemorrhage, sepsis due to disseminated
miliary tuberculosis, cor pulmonale or secondary amyloidosis.

19. SIGNS AND SYMPTOMS:
• Cough for 3 weeks or more/productive cough
• Sputum usually mucopurulent/purulent
• Haemoptysis
• Fever with night sweats
• Tiredness
• Weight loss
• Anorexia
• Malaise

20. MANAGEMENT OF TUBERCULOSIS:
In treating tuberculosis, a number of factors are important:
1. Choice of drugs
2. Length of treatment
3. Co-morbidity especially HIV infection, liver and renal diseases
4. Adherence to treatment by the patient
Drug treatment: Treatment with anti-TB drugs has 2 main purposes:
1. To cure people with TB, provided the bacilli are drug sensitive.
2. To control TB, by either preventing the development of infectious forms
or reducing the period of infectivity of people with infectious disease.

21. FIRST-LINE DRUGS:
1. Isoniazid(H)
2. Rifampicin(R)
3. Pyrazinamide(Z)
4. Ethambutol(E)
5. Streptomycin(S)

22. 1. ISONIAZID:
MOA: Isoniazid inhibits biosynthesis of mycolic acid, which is an
essential component of mycobacterial cell wall and results in the death
of bacteria (tuberculocidal). It is active against both intracellular and
extracellular bacilli.
ADRs: Peripheral neuropathy, hepatotoxicity, skin rashes, arthralgia, GI
disturbances, psychosis and rarely convulsions.
Dose: 5-10mg/kg or a maximum dose of 300mg/day

23. 2. RIFAMPICIN:
MOA: Rifampicin binds to the beta subunit of the DNA dependent RNA
polymerase enzyme and inhibits m-RNA synthesis in the bacteria. It has
bactericidal effect. It is active against both intracellular and
extracellular bacilli.
ADRs: Hepatotoxicity, GI disturbances, flu-like syndrome, headache,
drowsiness, dizziness, nausea, vomiting, hypersensitivity reactions etc.
Dose: 15-20mg/kg or a maximum dose of 450-600mg/day

24. 3. PYRAZINAMIDE:
MOA: Pyrazinamide is converted to its active form/active metabolite
pyrazinoic acid by the enzyme pyrazinamidase present in the
mycobacteria. This metabolite may inhibit the synthesis of mycolic acid
by the mycobacteria. It requires an acidic pH (5.5) for its tuberculocidal
activity.
ADRs: Dose dependent hepatotoxicity, anorexia, nausea, vomiting,
fever, skin rashes, malaise, urticaria, arthralgia etc.
Dose: 25-40mg/kg or a maximum dose of 3g/day

25. 4. ETHAMBUTOL:
MOA: Ethambutol inhibits mycobacterial arabinosyl transferase
(encoded by emb gene) enzyme, which is involved in the
polymerization reaction of the arabinoglycan, an essential component
of mycobacterial cell wall. It is tuberculostatic and acts on fast
multiplying bacilli in the cavities. It is also effective against atypical
mycobacteria (mutation of emb gene).
ADRs: Optic neuritis, hypersensitivity reactions like skin rashes, itching
etc., fever, arthralgia, GI disturbances, headache, mental disturbances
etc.
Dose: 15-25mg/kg or a maximum dose of 800-1200mg/day

26. 5. STREPTOMYCIN:
MOA: It irreversibly inhibits bacterial protein synthesis in atleast 3
ways:
1. Interference with the initiation complex of peptide formation.
2. Misreading of m-RNA, which causes incorporation of incorrect
amino acids into the peptide, resulting in a non-functional or toxic
protein.
3. Breakup of polysomes into non-functional monosomes.
ADRs: Dose related ototoxicity, nephrotoxicity, ataxia, vertigo, rashes,
fever, renal impairment etc.
Dose: 15mg/kg or a maximum dose of 0.75-1gm/day

27. SECOND-LINE DRUGS:
1. Ethionamide
2. Cycloserine
3. Para-amino salicylic acid
4. Rifabutine and rifapentine
5. Fluoroquinolones: ciprofloxacin, levofloxacin, moxifloxacin,
ofloxacin
6. Injectable drugs: capreomycin, kanamycin, amikacin
7. Newer drugs: bedaquiline, pretomanid

28. Contd...
Consider second-line drugs, if:
• Resistance to first-line agents.
• Failure of clinical response to conventional therapy.
• Serious treatment-limiting ADR.
• Expert guidance available for toxic effects.

29. 1. ETHIONAMIDE:
MOA: Ethionamide upon oxidation with catalase-peroxidase is
converted to an active acylating agent, ethionamide sulfoxide, which
inturn activate inhA enoyl reductase and hence inhibits the synthesis of
mycolic acids. It is a tuberculostatic drug which is effective against both
intracellular and extracellular organisms.
ADRs: Intense gastric irritation, optic neuritis, hepatotoxicity.
Dose: 15mg/kg or a maximum dose of 0.75-1g/day

30. 2. CYCLOSERINE:
MOA: It inhibits the incorporation of D-alanine into peptidoglycan
pentapeptide by inhibiting the enzyme alanine racemase, which
converts L-alanine to D-alanine and finally inhibits mycobacterial cell
wall synthesis (tuberculostatic).
ADRs: CNS dysfunction including depression and psychosis, peripheral
neuropathy, seizures, tremors etc.
Dose: 15mg/kg or a maximum dose of 1g/day

31. 3. PARA-AMINO SALICYLIC ACID (PAS):
MOA: It is structurally similar to P-amino benzoic acid (PABA) and
sulfonamides. It shows similar action of sulphonamide. PAS inhibits
folate synthase enzyme, which is essential for the conversion of PABA
to dihydro folic acid (DHFA) and inhibits the synthesis of cell wall
(tuberculostatic activity).
ADRs: GI effects like nausea, anorexia, epigastric pain, diarrhoea, fever,
joint pain, hepatospleenomegaly, hepatitis, granuloytopenia,
adenopathy, peptic ulcers, gastric haemorrhage etc.
Dose: 200mg/kg or a maximum dose of 10-12g/day

32. 4. RIFABUTINE & RIFAPENTINE:
MOA: They are derived from rifamycin and related to rifampicin &
show similar mechanism of action of rifampicin i.e., bacterial RNA
polymerase enzyme inhibitors. These are weak enzyme inducers of CYT
P450 enzymes.
ADRs: Hepatotoxicity, GI disturbances, flu-like syndrome, nausea,
headache, vomiting, drowsiness, dizziness, hypersensitivity reactions
etc.
Dose: 300mg/day

33. 5. FLUOROQUINOLONES:
MOA: They are active against typical and atypical mycobacteria. They inhibit
inhibit the bacterial DNA synthesis by inhibiting bacterial topoisomerase-II
(DNA gyrase) and topoisomerase-IV. They have tuberculocidal activity.
ADRs: Nausea, vomiting, diarrhoea, headache, dizziness, skin rashes,
photosensitivity, damage growing cartilage, tendon rupture, insomnia etc.
Dose:
• Ciprofloxacin-750mg, BD, PO
• levofloxacin-500mg, OD, PO
• Moxifloxacin-400mg, OD, PO
• Ofloxacin-400mg, BD, PO

34. 6. INJECTABLE DRUGS:
MOA: These are aminoglycosides and their mechanism of action is
similar to streptomycin.
ADRs: Ototoxicity, nephrotoxicity, fever, rashes etc.
Dose:
• Capreomycin-15mg/kg or a maximum dose of 0.75-1g/day
• Kanamycin-15mg/kg or a maximum dose of 0.75-1g/day
• Amikacin-15mg/kg or a maximum dose of 1g/day

35. 7. NEWER DRUGS:
a) BEDAQUILINE:
MOA: Bedaquiline binds to oligomeric and proteolipid subunit-c of
mycobacterial ATP synthase, leads to the inhibition of ATP synthesis
and death of bacteria (tuberculocidal).
ADRs: Increased QT interval, abnormal and fatal heart rhythm
(increased risk of death), nausea, joint pain, headache and increased
liver enzymes.
Dose: 100mg oral

36. b) PRETOMANID:
MOA: It is a bicyclic nitroimidazole-like molecule. It is active against
both replicating and non-replicating organisms. It inibits mycolic acid
synthesis through unknown molecular mechanisms and inhibits cell
wall synthesis (like isoniazid).
ADRs: No ADRs are noticed. It is relatively safe, well-tolerated and
efficacious.
Dose: 100-200mg/day

37. TREATMENT REGIMEN:
The recommended standard regimen for respiratory and most other
forms of tuberculosis in UK is:
1. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol for the initial 2
months (initial phase).
2. A further 4 months of Rifampicin and Isoniazid (continuous phase).

38. Contd...
INITIATION PHASE
• 2-3 months
• 4-5 drugs
• Rapidly kills bacilli
• Isoniazid
• Rifampicin
• Ethambutol
• Pyrazinamide
CONTINUOUS PHASE
• 4-6 months
• 2-3 drugs
• Eliminates remaining bacilli
• Prevents relapse
• Isoniazid + pyridoxine
• Rifampicin

39. DIRECTLY OBSERVED THERAPY (DOT):
DOT, where the patient is observed taking their anti-tuberculous
medication by a health care professional. But it is not needed for more
cases of active TB. A risk of assessment for treatment adherence should
be undertaken in all patients and DOT regimens considered where non-
adherence to treatment might be a problem.
e.g. In street or shelter dwelling homeless people with active TB and in
patients with a history of non-adherence (individuals with chronic
alcohol or other social problems).
Advantages: High cure rate, decreased drug resistance, ADRs can be
monitored

40. REFERENCES/BIBLIOGRAPHY:
• Text book of pathology by Harsh Mohan
• Clinical Pharmacy and Therapeutics – Roger and Walker, Churchill
Livingstone publication
• Pharmacotherapy: A Pathophysiologic approach – Joseph T. Dipiro