isoniazid

see also:

• isoniazid overdose
• tuberculosis (TB)
• antibiotics

• isoniazid (INH) has bacteriostatic activity against Mycobacterium tuberculosis and is one of the first line chemotherapeutic agents used in treating tuberculosis (TB)
• high doses may cause pyridoxine (vitamin B6) deficiency states
• isoniazid overdose results in reduced CNS GABA and seizures and coma which requires high dose iv pyridoxine (vitamin B6) to Rx.

• readily and completely absorbed when given orally (but reduced when taken with food)
• peak blood levels within 1-2hrs
• plasma half-life 1-4hrs, longer if slow inactivators, impaired hepatic or renal function
• readily crosses BBB and placenta
• metabolised primarily by acetylation and dehydrazination
  • rate of acetylation is genetically determined:
    • 50% of Blacks and Caucasians are slow inactivators who may have higher blood levels of the drug, and thus an increase in toxic reactions
    • most Eskimos and Orientals are rapid inactivators but this is not clinically relevant
  • newborn infants have limited acetylation capacity, which results in a prolonged elimination half-life of isoniazid

• drug-induced hepatitis or HS reactions to INH
• PH severe reactions to INH such as drug fever, arthritis
• acute liver disease of unknown origin

• severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment
  • risk increases with age and daily alcohol consumption
• carefully monitor in patients who:
  • are receiving phenytoin or carbamazepine concurrently
  • are daily users of alcohol
  • have severe renal dysfunction
  • have chronic liver disease
  • are > 50yrs age
• ophthalmological examinations (including ophthalmoscopy) should be done before isoniazid is started and periodically thereafter, even without occurrence of visual symptoms as there is risk of optic neuritis.
• category A in pregnancy - should be prescribed during pregnancy only when therapeutically necessary
• lactation - monitor infants as INH passes readily into breast milk
• newborn infants have limited acetylation capacity and thus at risk of toxicity

• phenytoin - increased serum phenytoin levels and toxicity
• carbamazepine - increased serum carbamazepine levels and toxicity
• ethanol (alcohol and alcohol withdrawal) - increased risk of hepatotoxicity
• rifampicin - increased risk of hepatotoxicity
• paracetamol (acetaminophen) - INH may increase risk of paracetamol toxicity

• dose related peripheral neuropathy is the most common side effect
  • risk highest in slow acetylators, uraemics, malnourished patients, alcoholics and diabetics
  • uncommon with doses of isoniazid less than 5 mg/kg
  • those at risk should receive 100 to 300 mg of pyridoxine (vitamin B6) daily
• elevated LFTs
• hepatitis
• agranulocytosis
• haemolytic, sideroblastic or aplastic anaemia;
• thrombocytopenia
• eosinophilia
• drug fever
• skin eruptions
• lymphadenopathy
• vasculitis
• gynaecomastia
• hyperglycaemia
• pyridoxine (vitamin B6) deficiency states / pellagra
• risk of INH toxicity

• adults: 4-6mg/kg daily in divided doses (max. 300mg/day)
  • in TB meningitis, up to 10mg/kg/day can be given for 1st 1-2 wks of Rx
• children: 5-20mg/kg daily in divided doses