Author: chiara benevenuta
Date: 05/07/2011



Isoniazid (Isonicotinic acid hydrazide.) is a powerful first-line antitubercular agent, commonly used in association with Rifampicin , Pyrazinamide , Ethambutol.
INH is now available worldwide, it’s inexpensive and generally well tolerated.

Although INH shows a slight antidepressant activity, it does not inhibit MAO.
Discovery of IMAO anti-depressant drugs is due to studies on Iproniazide., a closely related complex that inhibits mycobacterial proliferation too, but is too toxic to be of common use.
It has been suggested that MAO inhibiting action of MAOIs may be secondary to some other factor that can explain both INH and Iproniazid antidepressant activity. However, this property remains undefined.




  • when somministrated per os, Isoniazid is rapidly and almost completely absorbed, and peak blood levels are reached in about 1 or 2 hours. Bioavailability is reduced when isoniazid is administered with food or alluminium anti-acid complexes, so it should be given on an empty stomach
  • It diffuses readily into all body fluids (including pleural and ascitic), tissues, organs, and excreta (saliva, sputum and feces).
    It crosses the Blood Brain Barreer when inflammed.
    It concentrates in the infected tissue (including the granulomas), even for a long time.
    The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma.
  • Isoniazid is < 10% bound to plasma proteins.
  • It is metabolized in the liver via acetylation (see: polymorphisms of NAT2).
    Acetylation rate significantly modifies INH half life.
    Half life is longer in case of epathic disease or insufficiency.
  • About 95% of INH doses are excreted through the urine in 24 h, mainly as metabolites (acetyl-INH and isonicotinic acid, that result from acetylation and hydrolysis). Doses do not usually have to be adjusted in case of renal failure, since elimination is largely independent of renal function.
    Small amounts are also excreted through saliva, sputum, and feces.
    Isoniazid is removed by hemodialysis and peritoneal dialysis.


  • KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex.
    This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA , thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase.
    InhA has been demonstrated to be the primary target of INH.
    In the past 10 years, M. tuberculosis dihydrofolate reductase (DHFR) was thought also a target of INH, but a 2010 study conclusively demonstrated that DHFR is not relevant to the antitubercular activity of INH.
  • This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall constitution, and explains isoniazid high specificity for mycobacteria, since no other bacteria uses mycolic acid for its cell wall.
    INH inhibits catalase-peroxidase complex (the activating enzime), thus enhancing ROS possibilities to damage the cell. Exposition to INH causes loss of acid-resistance and reduces the lipidic methanol extraible fraction.
  • Isoniazid is bactericidal to rapidly-dividing mycobacteria but is bacteriostatic if the mycobacterium is slow-growing.
    Minimal bacteriostatic concentration is 0.025-0.05 μg/ml. Bacteria divide once or twice before the multipling process is over. Isoniazid is highly specific for Mycobacteria; to inhibit growth of other micro-organisms we need a concentration of about 500 μg/ml. Mycobacterium Kansasii is generally responsive to isoniazid, but MIC has to be checked before starting any treatment.
  • Isoniazid easily penetrates mycobacterial cell wall, so being considerably more performing than rifampicin.


  • INH activation requires epathic acetylation.
    There are two forms of the enzyme arilamine N-acetyl-tranferase (NAT2), a "fast" and a "slow" one, so that some patients metabolize the drug more quickly than others.
    About 35 alleles of NAT2 have been characterised, even if most of them are not correlated with clinically significant variation. The transmission is Autosomical Recessive.
    Hence, the half-life is bimodal with peaks at 1 hour and 3 hours (US population). Approximately 50% of blacks and Caucasians are slow inactivators; the majority of Inuit and Asians are rapid inactivators. The half-life in fast acetylators is 1 to 2 hours, while in slow acetylators it is 2 to 5 hours.
    half-life may be prolonged in liver disease.
  • acetylation rate has not been shown to significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood concentrations with chronic administration of the drug, with an increased risk of toxicity. (see also.)
    Recent studies suggest that determination of NAT2 genotype. might be clinically useful in the evaluation of patients at high risk of developing ADRs induced by INH


  • Adverse reactions include rash, abnormal liver function tests, hepatitis, sideroblastic anemia (p450 is required for porphyrin synthesis), high anion gap metabolic acidosis, peripheral neuropathy, mild central nervous system effects.
  • Isoniazid inhibits the P450 system, possibly causing many pharmacological interactions (phenytoin, disulfiram, paracetamol, carbamazepine, ketoconazole, theophylline, valproic acid, vitamins)
  • Since INH inhibits cyt P450, it's supposed to promote the efficacy of Contraceptives. However, it is often associated with Rifampicin, that is kown to induce cyt P450.
    Alternative means of birth control should be used when under treatment.


  • Peripheral neuropathy and CNS effects are due to pyridoxine (vitamin B6) depletion, but are uncommon at doses of 5 mg/kg.
    Isoniazid binds to pyridoxal-5-phosphate, the active form of pyridoxine, to form INH-pyridoxal hydrazones. Pyridoxal-5-phosphate is a cofactor for glutamic acid decarboxylase and GABA transaminase in the GABA synthetic pathway. INH overdose results in decreased pyridoxal-5-phosphate, decreased GABA synthesis, increased cerebral excitability, and seizures.
    Optical neuritis and atrophy can occur, as well as muscular spasm, ataxia, paresthesia and toxic encephalopathy.
    Co-ingestion of ethanol potentiates toxicity by enhancing degradation of phosphorylated pyridoxine.
    High risk situations such as diabetes, uremia, alcoholism, malnutrition, HIV-infection, pregnancy and Epilepsy may need supplementation in pyridoxine (10–50 mg/day).
    INH can induce psychotic disorders.
    Headache, poor concentration, weight-gain, poor memory, and depression have all been associated with isoniazid use.
    All patients and healthcare workers should be aware of these serious adverse effects, especially if suicidal thinking or behaviour are suspected.
  • Hepatotoxicity
    INH is metabolized by the liver mainly by acetylation and dehydrazination, into a variety of products that include acetylhydrazine, a potent hepatotoxin.
    These metabolites are excreted through urine. With long-term administration at therapeutic doses, INH can cause clinically significant liver injury in 1% of patients and elevated liver enzyme levels in 10-20% of patients.
    Hepatotoxicity can be avoided with close clinical monitoring of the patient.
  • Toxic effects of INH also result from inhibition of lactate dehydrogenase, an enzyme that converts lactate to pyruvate, and from inhibition of cytochrome P450. Pharmacogenetic studies suggest that patients with certain cytochrome P450 genotypes may be more predisposed to hepatotoxicity.
    In vitro studies of a variety of animal cell lines demonstrated that INH toxicity results from the induction of apoptosis with associated disruption of mitochondrial membrane potential and DNA strand breaks.


  • In vitro growing mycobacteria soon develop isoniazid resistance even if treated with elevated doses, but no cross resistance. The switch from sensible microorganisms to resistant ones can take a few weeks of isoniazid monotherapy.
    The most common resistance mechanism consists of a mutation of the catalase-peroxidase (Katg) that reduces its activity, preventing prodrug convertion in its activated form.
    Another mechanism involves missense mutation of bacterial genes inhA and KasA, involved in mycolic acid synthesis.
    NADH dehidrogenase mutations cause isoniazid resistance too.


  • Goodman & Gilman "The Pharmacological Basis of Therapeutics" - Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy
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