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.
• Isoniazid is bacteriostatic for resting bacilli, but is bactericidal for rapidly dividing microorganisms.
• 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)
• INH & rifampin is active against extracellular as well as intracellular organisms.
• Pyrazinamide is more active against intracellular organism.
• Streptomycin acts only on extracellular bacilli

Isoniazid and rifampicin reach into the caseous material.

• 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.
• These genes are involved in mycolic acid biosynthesis in the bacteria.
• 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.
• 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.
• Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits gneration of pyridoxal phosphate.
• 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.

• Isoniazid,Rifampicin and Pyrazinamide can cause Hepatotoxicity but Pyrazinamide is the most Hepatotoxic.
  

Optic Neuritis and Atrophy.

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