· 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.
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 Thiacetazone (Thz)
o Ofloxacin (Ofx)
o Levofloxacin (Lvx or Lfx)
o Moxifloxacin (Mfx)
o Ciprofloxacin (Cfx)
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.
· 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.
3 times per week dose
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.
Mechanism of action
· Inhibit mycolic acid synthesis (Cell wall synthesis inhibition).
· 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.
· Loss of visual activity / color vision
· 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
· Interfere with the cell wall synthesis.
· Neuropsychiatric manifestation.
· Suicidal tendencies, convulsion, psychosis.
· 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
· MOA: inhibition of folate synthetase.
· Side effect: Hematological (Megaloblastic anemia)
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.
Hi….!! My name is Smrutiranjan Dash, From Odisha, India. Professionally I am Assistant Professor at The Pharmaceutical College, Barpali, Odisha, department of Pharmacology.