Anti-Tubercular drugs

Anti-Tubercular drugs

·         Tuberculosis is a granulomatous disease and a major health problem in developing countries.

·         About 1/3rd of the world’s population is infected with tuberculosis.

·         The causative organism Mycobacterium tuberculosis.


A.    First line drugs

·         It has high anti-tubercular efficacy as well as low toxicity.

·         Example:

o   Isoniazid (H)

o   Rifampicin (R)

o   Pyrazinamide (Z)

o   Ethambutol (E)

o   Streptomycin (S)

B.  Second line drugs

·         These drugs have either low anti-tubercular efficacy or higher toxicity or both and are used in special circumstances only.

o   Ethionamide (Eto)

o   Prothionamide (Pto)

o   Cycloserine (Cs)

o   Para amino salicylic acid (PAS)

o   Rifabutin

o   Terizidone

o   Thiacetazone (Thz)

·         Fluoroquinolones

o   Ofloxacin (Ofx)

o   Levofloxacin (Lvx or Lfx)

o   Moxifloxacin (Mfx)

o   Ciprofloxacin (Cfx)

·         Injectable

o   Kanamycin (Km)

o   Amikacin (Am)

o   Capreomycin (Cm)

·         Mycobacterium is derived from Greek word “Mycos” that means waxy appearance due to composition of their cell wall.

·         More than 60% of the cell wall is lipid mainly mycolic acid.

 Pathophysiology of tuberculosis

·         Entry of M. tuberculosis into the host.

·         Inside the lymph node alveolar macrophage develops by the M. tuberculosis.

·          Primary infection occur.

·         Formation of Granuloma and mutation.

Isoniazid (Isonicotinic acid hydrazide. H)

·         It is a primary tuberculocidal.

·         Freely soluble in water.

·         Bactericidal for actively growing tubercle bacilli.

·         Penetrates into macrophages and is active against both extracellular and intracellular organism.

Mechanism of action

·         INH is inhibited the synthesis of mycolic acid which are unique fatty components of mycobacterial cell wall.

·         INH enters sensitive mycobacteria which converts it by a catalase-peroxidase enzyme into a reactive metabolites.

·         Adduct with NAD that inhibit InhA (Enol-acetyl-carrier-protein-reductase) and KasA (Acyl-carrier-protein-kinase).


·         Also adduct with NADPH, which inhibit Mycobacterial DHFRase resulting interrupting of DNA synthesis.


·         Increase expression of InhA or by mutations that lower the enzyme’s affinity to NADH.


·         INH completely absorbed orally.

·         Penetrate all the body tissue, tubular cavities, placenta, and meninges.

·         Extensively metabolized in liver, most important pathway being N-acetylation.

·         The acetylated metabolic is excreted in urine.

·         The rate of INH acetylation show genetic variation.

                    i.            Fast acetylator

(30-40% of Indians) t1/2 of INH 1hr.

                  ii.            Slow acetylator

(60-70% of Indians) t1/2 of INH 3hrs.

·         Isoniazid induced peripheral neuropathy is more common in slow acetylator.

Adverse effects

·         Hepatitis

·         Rare in children, more in older people and alcoholics (chronic alcoholism induce CyP2E1 which generates the hepatotoxic metabolism).

·         Hepatotoxicity due to dose related damage to liver cell.

·         Peripheral Neuritis

o   Due to interference with production of the active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion in urine.

·         Pyridoxine given prophylactically (10mg/day)

o   Prevent the Neurotoxicity even with higher doses.

·         Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, lactating and HIV infected patients.



Daily dose

3 times per week dose





Isoniazid (H)

5 (4-6)


10 (8-12)


 Rifamycins: Rifampin, Rifabutin and Rifapetine

·         Rifampicin is derived from the soli mold Streptomyces.

·         It shows broader antimicrobial action than Isoniazid.

·         It is never given as a single drugs in the treatment of tuberculosis.

Mechanism of action

·         Rifampin blocks transcription by interacting with β subunit (involved in the binding of RNA polymerase to DNA) of bacteria, but not human, DNA dependent RNA polymerase (specific for prokaryotic).

·         Rifampin inhibit mRNA synthesis by suppressing the initiation step.

Antimicrobial spectrum

·         Having bactericidal effect for both intra and extracellular mycobacteria, like M. tuberculosis, M. Kansasii.

·         It also used for many gram +ve and gram –ve organisms.

·         Prophylactic used for Meningitis caused by meningococci or Haemophilus influenza.


·         Resistance to rifampin can be caused by a mutation in the affinity of the bacterial DNA-dependent RNA polymerase for the drug, or by decreased permeability.


·         Well absorbed orally.

·         Distribution occurs to all body fluids and organs.

·         Bioavailability is nearly 70%.

·         Food decreases absorption, so rifampin is to be take n in empty stomach.

·         Rifampin itself can induce the hepatic mixed-function oxidase, leading to a shortened half-life and numerous drug interaction.

·         Elimination via bile into the faces or via  the urine (secretion should be orange-red color)

Adverse effects

·         Nausea, Vomiting, Flushing and Rashes are most common.

·         Cholestasis jaundice (Excessive bilirubin stored in the skin and excreted throughout urine) and occasionally hepatitis.

·         Flu symptoms: chills, fever, headache, malaise (feeling discomfort and illness) and bone pain.

·         Urine color change to orange-red but is harmless.

Drug interaction

·         Rifampin induce several cytochrome p450 enzyme that can decrease the half-life of other drugs (like: Clofibrate, Digitoxin, Ketoconazole, Methadone, Oral contraceptives, prednisone propranolol, quinidine, and sulfonylureas warfarin).

·         These may leads to higher dose may require for these case.


·         Pyrazinamide chemically similar to INH

·         Having tuberculocidal property

·         More active in acidic medium.

·         Pyrazinamide enzymatically hydrolyzed to pyrazinoic acid, which is the active form of the drug.

·         Active against tubercle bacilli in acidic medium of lysosome, as well as in macrophages.

Mechanism of action

·         Inhibit mycolic acid synthesis (Cell wall synthesis inhibition).

Adverse effect

·         Hepatotoxicity

·         Hyperuricemia (High uric acid level in the blood)

·         Abdominal distress: arthralgia (Pain in joint), flushing, rashes, fever and loss of diabetic control.


·         Bacteriostatic and specific for most strains of M. tuberculosis and M. Kansasii.

Mechanism of action

·         Inhibit arabinosyl transferase, so that interfere with the synthesis of the Mycobacteria arabinogalactan cell wall.


·         Absorbed on oral administration.

·         Well distributed throughout the body.

·         Penetration into the CNS.

·         Both parent drugs and metabolites are excreted by glomerular filtration and tubular secretion.

Adverse effect

·         Loss of visual activity / color vision

·         Hyperuricemia


·         Tuberculocidal

·         Acts only on extracellular bacilli (because poor penetration into cells).

·         It penetrate tubular cavities, but does not cross to the CSF, and has poor action in acidic medium.

·         Streptomycin also considered as a second line drugs, because it more effective than first line agents and their toxicity often more serious.

Second line drugs


·         Bacteriostatic


·         Interfere with the cell wall synthesis.

Side effect

·         Neuropsychiatric manifestation.

·         Suicidal tendencies, convulsion, psychosis.

·         Nephrotoxicity


·         It the structural analogous of INH

·         Ethionamide can inhibit acetylation of INH.

·         Effective after oral administration.

·         Widely distributed in body, including CSF.

·         Neurological side effect: Psychosis

·         Hepatitis.


·         MOA: inhibition of folate synthetase.

·         Side effect: Hematological (Megaloblastic anemia)

·         Hypothyroidism

·         Hepatitis

·         Hypokalemia

·         Hypersensitivity

Management of Tuberculosis

Short course chemotherapy (DOTS – Direct Observed Therapy)

·         WHO introduced DOTS programme in 1995, under which 6-8 months multi drugs ‘short course’ regiments are framed.

·         According to severity the patients are divided into four categories.

·         Category I: New case of sputum smear positive or severe pulmonary TB, or severe forms of extra pulmonary TB (meningitis, etc.).

·         Category II: Defaulted, irregularly treated and relapse cases.

·         Category III: New sputum smear negative pulmonary TB and less severe forms of extra pulmonary TB (glandular/skin TB, etc.).

·         Category IV: Chronic cases who remained or again became sputum smear positive after receiving fully supervised category II treatment.

Tuberculosis management according to WHO (2010)

Tuberculosis in pregnant women

·         2HRE + 7HR (Total 9 months)

·         Contraindicated because it is ototoxicity to the fetus.

·         ‘Z’ is not recommended (due to lack of adequate teratogenicity)

 Treatment of breast feeding women

·         All anti-TB drug are comparable, but baby should watched.

·         Baby should receive BCG vaccination and 6 month INH preventing treatment after ruling out active TB.


·         Standard drugs: H – 300mg (10 mg/kg in children) daily for 6 months.

·         INH resistance: Combination drug H (5mg/kg) and R (10mg/kg, maximum 600 mg) daily for 3 months.

Tuberculosis in AIDS patients

·         Daily HRZE for 2 month: started immediately on the diagnosis of TB followed by continuous phase of HR for 4-7 months (Total 6-9 months)

·         Pyridoxine 25-50mg/ daily + INH, counteract neurological side effects.

·         Rifabutin (less potent enzyme inducer) given 9-12 months may be substituted for Rifampicin.





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