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.
First line drugs
It has high anti-tubercular efficacy as well as low toxicity.
Second line drugs
These drugs have either low anti-tubercular efficacy or higher toxicity or both and are used in special circumstances only.
Para amino salicylic acid (PAS)
Levofloxacin (Lvx or Lfx)
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.
Fast acetylator (30-40% of Indians) t1/2 of INH 1hr.
Slow acetylator (60-70% of Indians) t1/2 of INH 3hrs.
Isoniazid induced peripheral neuropathy is more common in slow acetylator.
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.
Due to interference with production of the active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion in urine.
Pyridoxine given prophylactically (10mg/day)
Prevent the Neurotoxicity even with higher doses.
Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, lactating and HIV infected patients.
Daily dose: 5(4-6) mg/kg, Maximum 300 mg
Three time per week dose: 10 (8-12), Maximum 900 mg
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.
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)
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.
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.
Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Presently I am working as an Assistant Professor at The pharmaceutical college, Barpali.