Isoniazid(INH)

ISONIAZID(INH)
  • Isoniazid is considered the primary drug for the chemotherapy of tuberculosis.
  • Isoniazid is the drug of choice for prophylaxis of TB
  • MDR is defined as resistance INH and rifampicin with or without resistence to other drugs
  • For diagnosis of MDR TB, currently drug sensitivity testing is done for Rifampicin,Isoniazid,Streptomycin and Ethambutol.
  • XDR(Extreme Drug Resistant TB) is defined as resistance to INH and rifampicin as well as to all fluoroquinolones and one of injectable drugs (capreomycin, kanamycin, amikacin). In a patient with suspected tubercular anterior uveitis the diagnosis is confirmed by a positive response to isoniazid test.
  • A poverty-stricken mother suffering from active tuberculosis delivers a baby. Breast feeding + INH + BCG vaccination would be the most appropriate in her case
MECHANISM OF ACTION OF ISONIAZID
  • It is a Bactericidal drug.
  1. Isoniazid is bacteriostatic for resting bacilli, but is bactericidal for rapidly dividing microorganisms.
  2. The bactericidal action of rifampicin covers all subpopulations of TB bacilli.
  • It is the most effective antitubercular drug against slow multiplying intracellular mycobacteria It is the most effective drug against Extracellular Mycobacteria and Intracellular Mycobacteria(due to the leaset inhibitory concentration of Isoniazid required as compared to other drugs)
  1. INH & rifampin is active against extracellular as well as intracellular organisms.
  2. Pyrazinamide is more active against intracellular organism.
  3. Streptomycin acts only on extracellular bacilli
  • Isoniazid and rifampicin reach into the caseous material.
  1. But, rifampicin is the most effective drug in caseous material as it is bactericidal aganist both dividing and dormant (non-dividing) bacterial. Whereas, INH is effective (cidal) only on dividing bacteria but is static for non-dividing (dormant) bacteria.
DOSE OF ISONIAZID Dose of Isoniazid in children
  • 10-20mg/kg when given daily. Maximum dose is 300mg/d. When given twice or thrice, weekly dose is 20-40mg/kg maximum of 900mg.
Dose of Isoniazid in Adults 
  • 5 mg/kg (up to 300 mg) IM or orally once a day, or 15 mg/kg (up to 900 mg) 2 to 3 times a week in active infection.
  • 10-20 mg/kg/day orally once a day, not to exceed 300 mg/day in Latent infection.
  • 300 mg orally once a day or 900 mg orally 2 to 3 times a week in prophylaxis.
METABOLISM OF ISONIAZID
  • Isoniazide is metabolized by Acetylation.
MECHANISM OF ISONIAZID RESISTANCE
  • The most common cause of resistance in Isoniazid is mutation of the kat G gene.
  • kat G gene codes for catalase-peroxidase that activates the isoniazid (isoniazid is a prodrug).
  • Another mechanism of resistance in Isoniazid is related to mutation in the mycobacterial inh A and kas A genes.
  1. These genes are involved in mycolic acid biosynthesis in the bacteria.
  2. Mutation in the genes involved in the biosynthesis of mycolic acid will result in different variety of mycolic acid which cannot be killed by the Isoniazid.
  3. The unique feature of mutation in inh A gene is that it also leads to cross resistance to Ethionamide.Cross resistance of Isoniazid is seen with Ethionamide.
SIDE EFFECTS AND DRUG INTERACTIONS OF ISONIAZID Peripheral Neuropathy
  • Most common antitubercular drug which is implicated in causing peripheral neuropathy is INH.
  • Functional Pyridoxine/Vitamin B6 deficiency is the likely mechanism of INH-induced peripheral neuropathy.
  • Peripheral neuritis due to isoniazid is due to formation of Hydrazone complex.
  1. Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits gneration of pyridoxal phosphate.
  2. Isoniazid also combines with pyridoxal phosphate to interfere with its coenzyme function. Due to formation of hydrazones, the renal excretion of pyridoxine compounds is increased.
  • Peripheral neuropathy during use of Isoniazid might be prevented by using Pyridoxine
  • The treatment of this disorder is slow IV administration of 2-5 g of pyridoxine 
  • Pharmaceutical agents causing peripheral neuropathy :
  • Chloramphenicol,Colchicine,Dapsone,Disulfiram,Ethambutol,Ethionamide,Isoniazid,Metronidazole,Misonidazole,Nitrofurantoin,Nitrous oxide,Nucleoside analogues (ddC, ddl, 
  • 4dT),Pyridoxine,Suramin,Taxol,Thalidomide,Vincristine and other vinca alkaloids
Hepatitis.
  1. Isoniazid,Rifampicin and Pyrazinamide can cause Hepatotoxicity but Pyrazinamide is the most Hepatotoxic.
  2. Optic Neuritis and Atrophy.
  3. Lupus like syndrome
  • Lupus like picure can be caused by Isoniazid,Hydralazine and Procainamide.
Hemolytic anemia in G6PD deficiency.
  • Drugs causing hemolytic anaemia:Isoniazid,Sulfonamide,Procainamide , Phenacetin,Melphalan,Rifampicin,Quinidine,Penicillin and Dapsone
  • Seizure, ataxia, muscle twitching, toxic encephalopathy, psychoses, rashes, fever, arthralgia, acne,
  • Isoniazid inhibit phenytoin metabolism & can precipitate its toxicitiy.
 Exam Question
  • Isoniazid inhibit phenytoin metabolism & can precipitate its toxicitiy.. Cross resistance of Isoniazid is seen with Ethionamide.
  • Side -effects of Isoniazid are Peripheral Neuropathy,Hepatitis,Optic Neuritis.
  • Peripheral neuropathy during use of Isoniazid might be prevented by using Pyridoxine.
  • Multi drug resistance (MDR) TB is defined as resistance to Rifampicin and isoniazide
  • XDR(Extensively Drug Resistant TB) is defined as resistance to INH and rifampicin as well as to all fluoroquinolones and one of injectable drugs (capreomycin, kanamycin, 
  • amikacin).
  • For diagnosis of MDR TB, currently drug sensitivity testing is done for Rifampicin,Isoniazid,Streptomycin and Ethambutol.
  • Dose of Isoniazid in children is 10-20mg/kg when given daily.
  • Isoniazid is a Bactericidal Drug.
  • Isoniazid and rifampicin reach into the caseous material.
  • Isoniazid is the most effective drug against Extracellular Mycobacteria.
  • Rifampicin is the most effective antitubercular drug against slow multiplying intracellular mycobacteria.
  • Peripheral neuritis due to isoniazid is due to formation of Hydrazone complex.
  • Isoniazid is the drug of choice for prophylaxis of TB.
  • Isoniazide is metabolized by Acetylation.
  • In a patient with suspected tubercular anterior uveitis the diagnosis is confirmed by a positive response to isoniazid test.
  • Lupus like picure can be caused by Isoniazid,Hydralazine and Procainamide.
  • A poverty-stricken mother suffering from active tuberculosis delivers a baby. Breast feeding + INH + BCG vaccination would be the most appropriate in her case
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