Tuberculosis is caused by Mycobacterium tuberculosis and treated using a combination of drugs over several months. The RNTCP in India aims to eliminate TB by 2025 through a strategy of detecting, treating, preventing, and building systems. First line drugs include isoniazid, rifampicin, pyrazinamide, and ethambutol while second line drugs are used to treat drug resistant forms of TB like MDR-TB and XDR-TB. Treatment involves a two month intensive phase using multiple drugs followed by a four month continuation phase with fewer drugs.

1. ANTI – TUBERCULAR DRUGS
Tuberculosis is a chronic granulomatous disease caused by Mycobacterium tuberculosis.
RNTCP has released a ‘ National Strategic Plan for tuberculosis 2017-2025’ for control and
elimination of TB in India by 2025.
According to NSP TB elimination have been integrated into four strategic pillars of Detect –
Treat –Prevent – Build (DTPB)
Provision of free TB drugs in the form of daily fixed dose combinations (FDCs) for all TB
cases is advised with the support of directly observed treatment.
 First line treatment of drug sensitive TB consists of 2 months (8 weeks) intensive phase with
four drugs. FDC followed by a continuation phase of four months (16 weeks) with three drug
FDCs.
 For new TB cases the treatment in Intensive phase consists of eight weeks of Isoniazid (INH),
Rifampicin, Pyrazinamide and Ethambutol (HRZE) in daily doses as per four weight band
categories and in continuation phase three drug FDCs – Rifampicin, Isoniazid and Ethambutol
(HRE) are continued for 16 weeks.
 For previously treated case of TB intensive phase is of 12 weeks, where injection
Streptomycin is given for 8 weeks along with 4 drugs ( INH, Rifampicin, Pyrazinamide and
Ethambutol ) and after 8 weeks the four drugs Isoniazid ( INH, Rifampicin, Pyrazinamide and
Ethambutol ) in daily doses as per four weight band categories are continued for another 4
weeks. In continuation phase Rifampicin, Isoniazid and Ethambutol are continued for another
20 weeks as per daily doses.
 The continuation phase in both new and previously treated cases may be extended by 12 -24
weeks in certain forms of TB like skeletal, disseminated TB based on clinical decision of
treating physician.
Based on antitubercular activity, drugs may be grouped as :
• Tuberculocidal agents : Isoniazi, Rifampicin, Streptomycin, pyrazinamide,
capreomycin, kanamycin, ciprofloxacin
• Tuberculostatic agents : Ethambutol, ethionamide, thiacetazone, cycloserine, PAS.
Drugs used in TB
First line drugs
 Isoniazid  Ethambutol
 Rifampicin  Streptomycin
 Pyrazinamide

2. Second line drugs
• Ethionamide
• Thiacetazone
• Para-amino salicylic acid
• Amikacin
• Capreomycin
• Cycloserine
• Ciprofloxacin
• Bedaquiline
• Rifabutin
• Kanamycin
• Rifapentine
Isoniazid
• It is most effective and cheapest primary antitubercular drug.
• It destroys :
 Intracellular bacilli as it penetrates into the cells, i.e. tubercle bacilli in macrophages.
 Bacilli multiplying in the walls of the cavities.thus effective against both intra- and
extra -cellular organisms.
Mechanism of action INH
Enters mycobacteria
Active form
Binds enzymes
Inhibits mycolic acid synthesis
Weak cell wall

3. Bacteria killed (tuberculocidal)
Pharmacokinetics
• Completely absorbed orally
• Penetrates all tissues, tubercular cavities, necrotic tissues and CSF.
• Metabolized by acetylation.
• t1/2 is slow acetylators is 3-5 hrs while in fast acetylators it is 1 hr.
• Metabolites are excreted in urine.
Adverse effects
• Peripheral neuritis
• Hepatitis
• CNS toxicity in clude psychosis and seizures
• Other minor effects – anorexia, gastrointestinal discomfort, fever and allergic reactions
can occur.
• Hemolysis can occur in G6PD deficiency patients.
Rifampicin
• It is a semisynthetic derivative of rifamycin (an antibiotic).
Mechanism of action
Rifampicin
Binds DNA dependent RNA polymerase
Inhibits RNA synthesis
Bactericidal
Pharmacokinetics
• Well absorbed orally
• Bioavailability 70%
• Food decreases absorption, so should be taken empty stomach
• Widely distributed in the body: penetrates intracellularity, enters tubercular cavities,
caseous masses and placenta.

4. • Metabolized in liver
• Excreted mainly in bile, some in urine
• t ½ is variable (2-5 hrs)
Adverse effects
• Effects similar to INH
• Hepatitis , a major adverse effect , generally occurs in patients with preexisting liver
disease and is dose related
• Cutaneous syndrome : flushing, pruritus + rash , redness, and watering of eyes.
• Flu syndrome : with chills, fever, headache, malaise and bone pain
• Abdominal syndrome : nausea, vomiting, abdominal cramps with or without diarrhoea.
• Urine and secretions may become orange-red-nut this is harmless.
• Respiratory syndrome : breathlessness which may be associated with shock and
collapse.
• Purpura, haemolysis, shock and renal failure.
Pyrazinamide
• It is a tuberculocidal and is more active in acidic pH.
• Like INH it is also converted inside the mycobacterial cell into an active metabolite
pyrazinoic acid by an enzyme. This metabolite gets accumulated in acidic medium and
probably inhibits mycolic acid synthesis.
• It is effective against intracellular bacilli.
• If used alone resistance develops.
• Well absorbed (achieves good concentration in CSF)
• Hepatotoxicity is most common adverse effect.
• Hyperuricemia, arthralgia, anorexia, vomiting and rashes can be seen.
Pharmacokinetics
• Absorbed orally
• Widely distributed
• Good penetration in CSF
• Metabolized in liver
• Excreted in urine
• Plasma t ½ is 6-10 hrs.

5. Adverse Effects
• Hepatotoxicity
• Hyperuricaemia
• Gout can occur
• Abdominal distress
• Arthralgia
• Flushing
• Rashes
• Fever
• Loss of diabetes control
• Repeated glucose monitoring is warranted is diabetics.
Ethambutol
• It is tuberculostatic and acts on fast multiplying bacilli in the cavities. also effective
against atypical mycobacteria.
• It inhibits the incorporation of mucolic acids into the mycobacterial cell wall by
inhibiting certain enzymes involved in it.
Pharmacokinetics
 About ¾ of an oral dose of E is absorbed.
 Widely distributed
 Penetrates meninges incompletely and temporarily stored in RBCs.
 Less than ½ of E is metabolized
 Excreted in urine
 Plasma t ½ is 4 hrs
Adverse Effects
• Loss of visual acuity/colour vision
• Nausea
• Rashes
• Fever
• Rarely peripheral neuritis
• Hyperuricemia is due to interference with urate excretion.

6. Streptomycin (S)
 Active mainly against extracellular.
 Source: Streptomyces griseus
 First line anti TB drug, given by injection
Pharmacokinetics
 Penetrates into cells poorly & ineffective for intracellular tubercle bacilli.
 Crosses BBB & achieves therapeutic concentration if meninges are inflamed.
Para amino salicylic acid
Mechanism of action
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against
Mycobacterium tuberculosis.
It is structurally similar to p-amino benzoic acid (PABA) and the sulfonamides.
Pharmacokinetics
Absorption
Tmax is about 6 hours.
Distribution
About 50% - 60% is protein bound.
Elimination
 80% is excreted in the urine with at least 50% excreted in acetylated from.
 The t1/2 of free aminosalicylic acid is 26.4 min.
Dose
4g 3 times daily, children < 15 years: 200-300mg/kg daily in 2-4 divided doses.
Adverse reactions
GI: Nausea; vomiting; diarrhoea; abdominal pain
Metabolic: Goitre with or without myxedema.
Miscellaneous: Hypersensitivity (eg., fever, skin eruptions, leukopenia, thrombocytopenia,
hemolytic anemia, jaundice, hepatits, encephalopathy, Loffler syndrome, vasculitis)
Ethionamide
Mechanism of action
Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought
that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid.

7. Pharmacokinetics
 Absorption: Completely absorbed following oral administration.
 Bioavailability approx.. 100%.
 Volume of distribution 93.5 L
 Protein binding: Approx. 30% bound to proteins
 Metabolism: Hepatic; metabolised to the active metabolite sulfoxide, and several
inactive metabolites.
The sulfoxide metabolite has been demonstrated to have anti microbial activity against
Mycobacterium tuberculosis.
 Route of elimination: Less than 1% of the total dose is excreted as ethionamide in urine.
 Half life: 2 – 3 hours
Adverse reactions
>10%
 Disorder of GI tract (50%)
Frequency not defined
 Postural hypotension
 Dizziness
 Drowsiness
 Headache
 Peripheral neuropathy
 Psychosis
Contra-indications
 Hypersensitivity to ethionamide
 Severe hepatic dysfunction
Cautions
Diabetes mellitus, thyroid disease, hepatic impairment
Pregnancy & Lactation
 Pregnancy category: C
 Lactation: Excretion in milk unknown; use with caution
Cycloserine
It is an antibiotic produced by Streptomyces orchidaceous.
Mechanism of action

8.  It inhibits the incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting
alanine racemase, which converts L-alanine to D-alanine, and D-alanyl to D-alanine
ligase (finally inhibits mycobacterial cell wall synthesis).
 Cycloserine is used exclusively to treat TB caused by Mycobacterium tuberculosis
resistant to first line antigens.
Pharmacokinetics
 Distribution: CSF conc. Equal to that in plasma
 Metabolism: Liver
 Excretion: Urine
Interactions
Significant – Monitor closely
 Ethionamide
 Isoniazid
 Magnesium oxide / Anhydrous citric acid
Adverse reactions
Frequency not defined
 Confusion
 Dizziness
 Headache
 Somnolence
 Seizure
 Psychosis
Contra-indications
 Hypersensitivity
 Alcohol use
 Renal dysfunction, severe
 History of seizure disorder, mental depression, severe anxiety or psychosis
Cautions
 Alcoholism, anemia, impaired hepatic/renal function
Pregnancy & Lactation
 Pregnancy category: C
 Lactation: Enters breast milk; safe
Thioacetazone
Mechanism of action
Bacteriostatic – Inhibits cyclopropanaton of cell wall mycolic acids.

9. Uses
It continues to be used as a convenient low cost drug to prevent emergence of isoniazid
resistance, streptomycin & ethambutol.
Dose
150 mg OD in adults; 2.5 mg/kg in children; it is frequently combined with isoniazid.
T1/2 : 12 hours
Adverse reactions
Hepatitis, exfoliative dermatits, SJS, Bone marrow depression (rarely).
Common: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia

15. There are two main types, MDR TB and XDR TB.
• MDR TB is the name given to TB when the bacteria that are causing it are resistant to
at least isoniazid and rifampicin, two of the most effective TB drugs.
• XDR TB is defined as strains resistant to at least rifampicin and isoniazid. This is in
addition to strains being resistant to one of the fluoroquinolones, as well as resistant to
at least one of the second line injectable TB drugs amikacin, kanamycin or
capreomycin.
• MDR TB and XDR TB do not respond to the standard six months of TB treatment with
“first line” anti TB drugs. Treatment for them can often take two years or more and
requires treatment with other drugs that are less potent, more toxic and much more
expensive.
• RR-TB is Rifampicin resistant TB. Rifampicin resistant TB requires treatment with
second line drugs. Statistically RR-TB includes MDR-TB which is resistant to both
rifampicin and isoniazid.
• Mono-resistance: resistance to one first-line anti-TB drug only
• Poly-resistance: resistance to more than one first-line anti-TB drug, other than both
isoniazid and rifampicin