Isoniazid

July 22, 2020 Rima Pharmacology 0

  • Isoniazid also known as isonicotinic acid hydrazide (INH) is an antibiotic used in treatment of tuberculosis (TB). It has been mainstay of TB treatment in both children and adults.
  • Isoniazid was first synthesized in 1952. It is included in World Health Organization’s List of Essential Medicines and it is also available as generic medicine.
  • It is derivative of isonicotinic acid.
  • TB is an infectious disease caused by several species of mycobacteria including M. tuberculosis and M. bovis. It is world’s second commonest cause of death due to infectious disease after HIV/AIDS.

Mechanism of action and antibacterial spectrum of Isoniazid

Figure 1- Mechanism of action of Isoniazid

  • INH acts as bacteriostatic for resting bacilli and bactericidal for dividing microorganisms.
  • It acts as a prodrug. It enters mycobacterial cell by passive diffusion where it is activated by mycobacterial catalase-peroxidase (KatG) into an active metabolite. This active metabolite targets the enzyme acyl carrier protein (ACP) reductase and β-ketoacyl-ACP synthase which play important role in synthesis of mycolic acid.
  • Mycolic acid is unique to mycobacterium cell wall. It is long branched lipid attached to unique polysaccharides in mycobacterium cell wall. Inhibition of mycolic acid results in disruption of bacterial cell wall.
  • INH also inhibit same catalase-peroxidase and makes organism susceptible to oxidative mechanism.
  • It is specific for treatment of tuberculosis. It may be effective against M. kansasii at higher concentration.
  • Most NTM (Non-Tuberculosis Mycobacterium) are resistant to INH.

Resistance

  • INH resistance may occur due to following reasons:
    • Mutation or deletion of KatG.
    • Over expression of the target enzyme acyl carrier protein reductase.
    • Varying mutation of acyl carrier proteins.
  • Cross resistance may occur between isoniazid and ethionamide.
  • Mostly, isoniazid when used alone lead to resistance. The resistance typically develops after few weeks of therapy but may vary.

Pharmacokinetics of Isoniazid

  • INH is rapidly absorbed after oral and parenteral administration. Its absorption from GI tract is so complete that both oral and parenteral dose produce comparable plasma and tissue level.
  • GI absorption may be interfered by food (containing high amount of fat) and antacids. Peak plasma level reaches within an hour.
  • It diffuses readily into all body fluids and cells including saliva, milk, CSF (cerebrospinal fluid), pleural fluids, ascitic fluids and caseous material (necrotic tissue resembling cheese that is produced in TB lesions). Drug concentration in CSF is like those of serum.
  • Metabolism takes place in liver by acetylation (acetyl isoniazid) and N-hydrolysis (isonicotinic acid). Isoniazid acetylation is genetically regulated. It is due to genetically controlled N-acetyl transferase in liver and intestine. In fast acetylators, half-life is around 1 hour and in slow acetylators, half-life is around 3-4 hours.
  • Rapid inactivation is generally found in Japanese, Eskimos and also in Indians. In rapid acetylators, significant first-pass effect is observed after oral administration of INH.
  • It is mainly excreted though urine.
  • The clearance of INH may be prolonged significantly in liver disease whereas it is not affected by renal impairment.

Therapeutic Uses of Isoniazid

  • INH is most important drug for treatment of tuberculosis. It is used as standard first-line therapy alone or in combination.
  • It is used as monotherapy for prophylaxis and in combination with other agents like rifampicin and pyrazinamide for treating active infection of tuberculosis.
  • INH is recommended in women with active tuberculosis who are pregnant or breastfeeding. It is safest anti-tuberculosis drug to use during pregnancy.

Adverse effects

  • The most serious adverse effect is hepatitis (liver damage) which can be fatal if left untreated. It is more common in elderly patients (˃ 50 years). Regular monitoring of hepatic function is recommended, and drug should be avoided if SGPT increases to 3 times more than normal level.
  • Peripheral neuropathy may occur due to relative pyridoxine (vitamin B6) deficiency. This causes paresthesia, anesthesia, burning and pain in extremities. It is more common in patients who are diabetic, undernourished or chronic alcoholics.

It can be avoided by supplementation of 25 to 50 mg of pyridoxine per day. Slow acetylators have greater risk for peripheral         neuropathy and hepatotoxicity.

  • Allergic or hypersensitivity reactions include fever, rashes, skin eruptions, jaundice and rarely blood dyscrasias.
  • INH stimulate the CNS and may precipitate convulsion in patients with history of seizure. It may precipitate psychotic symptoms like euphoria, transient loss of memory, loss of self-control and personality changes.

Drug Interaction

  • INH inhibits hepatic metabolism of drugs like phenytoin, carbamazepine and ethosuximide and potentiate adverse effects of these drugs.
  • It also interacts with disulfiram.
  • Concurrent administration with acetaminophen (paracetamol) may increase risk of paracetamol toxicity.

Contraindication

  • Contraindicated in patients who are allergic or hypersensitive to INH.
  • Contraindicated in patients with acute liver disease or history of hepatitis due to INH.
  • It should be used with caution in patients who are diabetic, malnourished, drink alcohol daily or in elderly patient.

References

  1. Timmins GS, Dereti V. Mechanisms of action of isoniazid. Molecular Microbiology. 2006; 62(5): 1220-1227.
  2. Weber WW, Hein DW. Clinical Pharmacokinetics of Isoniazid. Clinical Pharmacokinetics. 1979; 4: 401–422.
  3. Kiser JJ, Zhu R, Argenio, Cotton MF, Bobat R, McSherry HD, Madhi SA et al. Isoniazid pharmacokinetics, pharmacodynamics and dosing in South African infants. Ther Drug Monit. 2012; 34(4): 446–451.
  4. Denti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, et al. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania. PLoS ONE. 2015: 10(10): e0141002.DF [889 KB]
  5. Goldman AL, Braman SS. Isoniazid: A Review with Emphasis on Adverse Effects. Chest. 1972; 62(1): 71-177.
  6. Meyler’s Side Effects of Drugs (Sixteenth Edition). The International Encyclopedia of Adverse Drug Reactions and Interactions.2016: 341-350.
  7. Pharmacology and Pharmacotherapeutics. 24th edition.
  8. Goodman and Gillman Manual of Pharmacology and Therapeutics.
  9. Lippincott Illustrated Reviews Pharmacology, 6th edition.